|
Binding affinity against imipramine receptor was determined in homogenized rat cortex tissue using [3H]-imipramine as radioligand
|
Rattus norvegicus
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic compounds as selective antimuscarinics. 1. Structural requirements for selectivity toward the muscarinic acetylcholine receptor in a series of pirenzepine and imipramine analogues.
Year : 1987
Volume : 30
Issue : 8
First Page : 1378
Last Page : 1382
Authors : Eberlein WG, Trummlitz G, Engel WW, Schmidt G, Pelzer H, Mayer N.
Abstract : The M1-selective antiulcer drug pirenzepine (1) is a tricyclic compound with close resemblance to tricyclic psychotropic agents such as imipramine (2). Despite this fact, pirenzepine is devoid of any psychotropic effects, exhibiting measurable antagonistic effects in biochemical assays and receptor binding studies only toward the muscarinic receptor system. To understand how different groups in these tricyclic molecules affect binding affinities, a set of nine compounds structurally related to pirenzepine (1) and imipramine (2) has been selected for analysis, comprising three different tricycles and three different side chains. The compounds were tested for their affinity to the imipramine and muscarinic receptors in homogenized rat cortex tissue. The result of these studies suggests that it is the nature and placement of accessory groups that determine the differences in receptor recognition and the binding process. In the case of pirenzepine (1), preferential binding toward the muscarinic receptor is brought about by the endocyclic amide group, by the positioning of the protonated N atom of the side chain, and to a minor extent by the exocyclic amide group. From these findings a putative model for the explanation of selective binding of pirenzepine (1) to the muscarinic receptor has been derived.
|
Ability to displace [3H](-)-quinuclidinyl benzilate(QNB) from M2 receptor in rat heart homogenate
|
None
|
267.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biodistribution of iodine-125-labeled 1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate. A new ligand for the potential imaging of muscarinic receptors by single photon emission computed tomography.
Year : 1993
Volume : 36
Issue : 7
First Page : 848
Last Page : 854
Authors : McPherson DW, DeHaven-Hudkins DL, Callahan AP, Knapp FF.
Abstract : 1-Azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)- alpha-phenylacetate (IQNP, 3), an analogue of QNB in which a phenyl ring has been replaced with an iodopropenyl substituent, was prepared and evaluated in vitro and in vivo for m-AChR selectivity and specificity. High specific activity [125]IQNP ([125I]-3) was synthesized in greater than 60% yield utilizing an electrophilic iododestannylation reaction with hydrogen peroxide for the oxidation of iodide. In in vitro receptor binding studies, 3 demonstrated high affinity for M1 (Ki = 0.78 nM), M2 (Ki = 1.06 nM), and M3 (Ki = 0.27 nM) subtypes. In vivo biodistribution studies in female rats [125I]-3 demonstrated high uptake in areas rich in muscarinic receptors such as the brain (cortex and striatum) and the heart. Blocking studies were performed with a series of receptor specific agents and demonstrated that the uptake of [125I]-3 was selective and specific for cerebral muscarinic receptor rich areas and that the binding to m-AChR is reversible. The high-yield preparation and specificity and selectivity of high specific activity [125I]IQNP for muscarinic receptors suggest that this is an attractive new agent for potential imaging of cerebral receptors using single photon tomographic imaging (SPECT).
|
Affinity constant measured against M2 muscarinic receptor in rat heart r
|
None
|
794.33
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of some methoctramine-related tetraamines bearing a 11-acetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one moiety as antimuscarinics: a second generation of highly selective M2 muscarinic receptor antagonists.
Year : 1993
Volume : 36
Issue : 23
First Page : 3734
Last Page : 3737
Authors : Melchiorre C, Bolognesi ML, Chiarini A, Minarini A, Spampinato S.
|
Ability to displace [3H]N-methylscopolamine (NMS) from M3 receptor in rat submaxillary gland homogenate
|
None
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biodistribution of iodine-125-labeled 1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate. A new ligand for the potential imaging of muscarinic receptors by single photon emission computed tomography.
Year : 1993
Volume : 36
Issue : 7
First Page : 848
Last Page : 854
Authors : McPherson DW, DeHaven-Hudkins DL, Callahan AP, Knapp FF.
Abstract : 1-Azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)- alpha-phenylacetate (IQNP, 3), an analogue of QNB in which a phenyl ring has been replaced with an iodopropenyl substituent, was prepared and evaluated in vitro and in vivo for m-AChR selectivity and specificity. High specific activity [125]IQNP ([125I]-3) was synthesized in greater than 60% yield utilizing an electrophilic iododestannylation reaction with hydrogen peroxide for the oxidation of iodide. In in vitro receptor binding studies, 3 demonstrated high affinity for M1 (Ki = 0.78 nM), M2 (Ki = 1.06 nM), and M3 (Ki = 0.27 nM) subtypes. In vivo biodistribution studies in female rats [125I]-3 demonstrated high uptake in areas rich in muscarinic receptors such as the brain (cortex and striatum) and the heart. Blocking studies were performed with a series of receptor specific agents and demonstrated that the uptake of [125I]-3 was selective and specific for cerebral muscarinic receptor rich areas and that the binding to m-AChR is reversible. The high-yield preparation and specificity and selectivity of high specific activity [125I]IQNP for muscarinic receptors suggest that this is an attractive new agent for potential imaging of cerebral receptors using single photon tomographic imaging (SPECT).
|
Affinity constant measured against M3 muscarinic receptor in rat submaxillary gland
|
None
|
173.78
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of some methoctramine-related tetraamines bearing a 11-acetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one moiety as antimuscarinics: a second generation of highly selective M2 muscarinic receptor antagonists.
Year : 1993
Volume : 36
Issue : 23
First Page : 3734
Last Page : 3737
Authors : Melchiorre C, Bolognesi ML, Chiarini A, Minarini A, Spampinato S.
|
Affinity constant measured against M4 muscarinic receptor rat NG108-15 cells
|
None
|
34.67
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of some methoctramine-related tetraamines bearing a 11-acetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one moiety as antimuscarinics: a second generation of highly selective M2 muscarinic receptor antagonists.
Year : 1993
Volume : 36
Issue : 23
First Page : 3734
Last Page : 3737
Authors : Melchiorre C, Bolognesi ML, Chiarini A, Minarini A, Spampinato S.
|
Ability to displace [3H]pirenzepine (PZ) from M1 receptor in rat cortex homogenate
|
None
|
5.21
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biodistribution of iodine-125-labeled 1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate. A new ligand for the potential imaging of muscarinic receptors by single photon emission computed tomography.
Year : 1993
Volume : 36
Issue : 7
First Page : 848
Last Page : 854
Authors : McPherson DW, DeHaven-Hudkins DL, Callahan AP, Knapp FF.
Abstract : 1-Azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)- alpha-phenylacetate (IQNP, 3), an analogue of QNB in which a phenyl ring has been replaced with an iodopropenyl substituent, was prepared and evaluated in vitro and in vivo for m-AChR selectivity and specificity. High specific activity [125]IQNP ([125I]-3) was synthesized in greater than 60% yield utilizing an electrophilic iododestannylation reaction with hydrogen peroxide for the oxidation of iodide. In in vitro receptor binding studies, 3 demonstrated high affinity for M1 (Ki = 0.78 nM), M2 (Ki = 1.06 nM), and M3 (Ki = 0.27 nM) subtypes. In vivo biodistribution studies in female rats [125I]-3 demonstrated high uptake in areas rich in muscarinic receptors such as the brain (cortex and striatum) and the heart. Blocking studies were performed with a series of receptor specific agents and demonstrated that the uptake of [125I]-3 was selective and specific for cerebral muscarinic receptor rich areas and that the binding to m-AChR is reversible. The high-yield preparation and specificity and selectivity of high specific activity [125I]IQNP for muscarinic receptors suggest that this is an attractive new agent for potential imaging of cerebral receptors using single photon tomographic imaging (SPECT).
|
Affinity constant measured against M1 muscarinic receptor in rat cortex
|
None
|
6.457
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of some methoctramine-related tetraamines bearing a 11-acetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one moiety as antimuscarinics: a second generation of highly selective M2 muscarinic receptor antagonists.
Year : 1993
Volume : 36
Issue : 23
First Page : 3734
Last Page : 3737
Authors : Melchiorre C, Bolognesi ML, Chiarini A, Minarini A, Spampinato S.
|
Inhibition of [3H]NMS binding to cerebral cortex membranes which contain predominantly the muscarinic acetylcholine receptor M1
|
None
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : Binary antidotes for organophosphate poisoning: aprophen analogues that are both antimuscarinics and carbamates.
Year : 1989
Volume : 32
Issue : 7
First Page : 1522
Last Page : 1528
Authors : Leader H, Smejkal RM, Payne CS, Padilla FN, Doctor BP, Gordon RK, Chiang PK.
Abstract : Prophylaxis against organophosphate poisoning can be achieved by pretreatment with physostigmine or pyridostigmine, which are carbamates, and aprophen, which is an anticholinergic agent. Thus, a series of aprophen analogues was synthesized with carbamyl substitutions on the phenyl rings (carbaphens). The rationale behind this design is that such compounds might exhibit most of the therapeutic characteristics of aprophen, as well as the ability to protect prophylactically by chemically masking cholinesterase enzymes. Compounds 4 (dimethylhydroxycarbaphen), 15 (dimethylcarbaphen), and 16 (monomethylcarbaphen) were found to inactivate human butyrylcholinesterase in a time-dependent manner with potencies similar to those of physostigmine or pyridostigmine, and the latter two exhibited almost the same antimuscarinic profile as aprophen. In contrast to the potent inactivation of butyrylcholinesterase by these compounds, marginal inactivation of acetylcholinesterase activity was observed, and only at much higher drug concentrations. The noncarbamylated analogues had no effect on the activity of either cholinesterase. The carbaphen compounds are hence prototype drugs that can interact with either muscarinic receptors or butyrylcholinesterase. Furthermore, these compounds are prodrugs, since after carbamylation of the cholinesterase, the leaving group 14 (hydroxyaprophen) is a potent antimuscarinic itself.
|
Binding affinity for muscarinic acetylcholine receptor M1 by measuring displacement of [3H]QNB from guinea pig cerebral cortex
|
Cavia porcellus
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-Heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives as muscarinic antagonists. Synthesis and structure-activity relationships.
Year : 1995
Volume : 38
Issue : 3
First Page : 473
Last Page : 487
Authors : Nilsson BM, Sundquist S, Johansson G, Nordvall G, Glas G, Nilvebrant L, Hacksell U.
Abstract : A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for muscarinic and antimuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate [(-)-[3H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive muscarinic antagonists in the urinary bladder. The highest receptor binding affinity, Ki (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3-benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antimuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the muscarinic m1 receptor.
|
Inhibition of carbachol-induced release of alpha-amylase from pancreatic acinar cells from that of rat ileum contained the muscarinic acetylcholine receptor M2 subtypes
|
None
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : Binary antidotes for organophosphate poisoning: aprophen analogues that are both antimuscarinics and carbamates.
Year : 1989
Volume : 32
Issue : 7
First Page : 1522
Last Page : 1528
Authors : Leader H, Smejkal RM, Payne CS, Padilla FN, Doctor BP, Gordon RK, Chiang PK.
Abstract : Prophylaxis against organophosphate poisoning can be achieved by pretreatment with physostigmine or pyridostigmine, which are carbamates, and aprophen, which is an anticholinergic agent. Thus, a series of aprophen analogues was synthesized with carbamyl substitutions on the phenyl rings (carbaphens). The rationale behind this design is that such compounds might exhibit most of the therapeutic characteristics of aprophen, as well as the ability to protect prophylactically by chemically masking cholinesterase enzymes. Compounds 4 (dimethylhydroxycarbaphen), 15 (dimethylcarbaphen), and 16 (monomethylcarbaphen) were found to inactivate human butyrylcholinesterase in a time-dependent manner with potencies similar to those of physostigmine or pyridostigmine, and the latter two exhibited almost the same antimuscarinic profile as aprophen. In contrast to the potent inactivation of butyrylcholinesterase by these compounds, marginal inactivation of acetylcholinesterase activity was observed, and only at much higher drug concentrations. The noncarbamylated analogues had no effect on the activity of either cholinesterase. The carbaphen compounds are hence prototype drugs that can interact with either muscarinic receptors or butyrylcholinesterase. Furthermore, these compounds are prodrugs, since after carbamylation of the cholinesterase, the leaving group 14 (hydroxyaprophen) is a potent antimuscarinic itself.
|
Displacement of [3H]methylscopolamine binding to muscarinic M3 receptor in submaxillary salivary glands of rats.
|
Rattus norvegicus
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Quinolizidinyl derivatives of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one as ligands for muscarinic receptors.
Year : 1999
Volume : 9
Issue : 20
First Page : 3031
Last Page : 3034
Authors : Novelli F, Sparatore A, Tasso B, Sparatore F.
Abstract : Quinolizidinyl derivatives of the tricyclic systems characterizing pirenzepine and nuvenzepine, were prepared and tested as ligands for muscarinic M1, M2 and M3 receptors; 5,11-dihydro-11-[(S-lupinyl)-thioacetyl]-6H-pyrido[2,3-b][1, 4]benzodiazepin-6-one exhibited IC50 = 10 nM for M1 and 760 nM for both M2 and M3 subtypes. During the synthesis some interesting side compounds were isolated and characterized.
|
Tested for affinity constant against M3 muscarinic receptor in rat submaxillary gland using [3H]NMS
|
None
|
173.78
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological activity of methoctramine-related tetraamines bearing an 11-acetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one moiety: structural requirements for optimum occupancy of muscarinic receptor subtypes as revealed by symmetrical and unsymmetrical polyamines.
Year : 1994
Volume : 37
Issue : 20
First Page : 3363
Last Page : 3372
Authors : Minarini A, Bolognesi ML, Budriesi R, Canossa M, Chiarini A, Spampinato S, Melchiorre C.
Abstract : Tetraamines 5-13 and diamines 14-17 as well as monoamine 18 were synthesized, and their biological profiles at muscarinic receptor subtypes were assessed by functional experiments in isolated guinea pig left atrium (M2) and ileum (M3) and by binding assays in rat cortex (M1), heart (M2), and submaxillary gland (M3) homogenates and NG 108-15 cells (M4). An appropriate number and type of substituents on the terminal nitrogens of a tetraamine backbone afforded compounds, such as tripitramine (8) and dipitramine (6), which are endowed with different affinity and selectivity profiles. Tripitramine, a nonsymmetrical tetraamine, resulted in the most potent and the most selective M2 muscarinic receptor antagonist so far available (pA2 = 9.75 +/- 0.02; pKi = 9.54 +/- 0.08). However, it failed to discriminate between M1 and M4 muscarinic receptor subtypes (selectivity ratio: M2/M3, 1600-2200; M2/M1, 81; M2/M4, 41; M1/M3, 28; M4/M3, 55; M4/M1, 2). Dipitramine, another nonsymmetrical tetraamine bearing two substituents on the same terminal nitrogen, displayed the highest affinity for M1 muscarinic receptors (pKi = 8.60 +/- 0.15) and was able to differentiate, unlike 8, all four muscarinic receptor subtypes investigated (selectivity ratio: M1/M2, 5; M1/M3, 2700; M1/M4, 76; M2/M3, 260-520; M2/M4, 15; M4/M3, 35). The results are discussed in terms of a possible mode of interaction of tetraamines with muscarinic receptor subtypes.
|
Compound was tested for inhibiting [3H]N-Methyl-scopolamine Binding to Muscarinic receptor (M3) in Rat Submaxillary Gland
|
None
|
173.78
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological activity of some 4-DAMP- related compounds
Year : 1995
Volume : 5
Issue : 20
First Page : 2325
Last Page : 2330
Authors : Tumiatti V, Santi S, Recanatini M, Minarini A, Melchiorre C, Chiarini A, Budriesi R
|
Inhibition of binding of [3H]N-methylscopolamine to muscarinic receptor (M3) in rat submaxillary gland homogenates
|
None
|
173.78
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological activity of some tetraamines related to methoctramine and 4-DAMP
Year : 1995
Volume : 5
Issue : 8
First Page : 785
Last Page : 790
Authors : Melchiorre C, Minarini A, Spampinato S, Tumiatti V
|
Tested for affinity constant against M4 muscarinic receptor in NG 108-15 cell homogenates using [3H]NMS
|
None
|
34.67
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological activity of methoctramine-related tetraamines bearing an 11-acetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one moiety: structural requirements for optimum occupancy of muscarinic receptor subtypes as revealed by symmetrical and unsymmetrical polyamines.
Year : 1994
Volume : 37
Issue : 20
First Page : 3363
Last Page : 3372
Authors : Minarini A, Bolognesi ML, Budriesi R, Canossa M, Chiarini A, Spampinato S, Melchiorre C.
Abstract : Tetraamines 5-13 and diamines 14-17 as well as monoamine 18 were synthesized, and their biological profiles at muscarinic receptor subtypes were assessed by functional experiments in isolated guinea pig left atrium (M2) and ileum (M3) and by binding assays in rat cortex (M1), heart (M2), and submaxillary gland (M3) homogenates and NG 108-15 cells (M4). An appropriate number and type of substituents on the terminal nitrogens of a tetraamine backbone afforded compounds, such as tripitramine (8) and dipitramine (6), which are endowed with different affinity and selectivity profiles. Tripitramine, a nonsymmetrical tetraamine, resulted in the most potent and the most selective M2 muscarinic receptor antagonist so far available (pA2 = 9.75 +/- 0.02; pKi = 9.54 +/- 0.08). However, it failed to discriminate between M1 and M4 muscarinic receptor subtypes (selectivity ratio: M2/M3, 1600-2200; M2/M1, 81; M2/M4, 41; M1/M3, 28; M4/M3, 55; M4/M1, 2). Dipitramine, another nonsymmetrical tetraamine bearing two substituents on the same terminal nitrogen, displayed the highest affinity for M1 muscarinic receptors (pKi = 8.60 +/- 0.15) and was able to differentiate, unlike 8, all four muscarinic receptor subtypes investigated (selectivity ratio: M1/M2, 5; M1/M3, 2700; M1/M4, 76; M2/M3, 260-520; M2/M4, 15; M4/M3, 35). The results are discussed in terms of a possible mode of interaction of tetraamines with muscarinic receptor subtypes.
|
Displacement of [3H]NMS binding to human Muscarinic acetylcholine receptor M1 using membranes from transfected CHO cells
|
None
|
28.2
nM
|
|
Journal : J. Med. Chem.
Title : Identification and characterization of m1 selective muscarinic receptor antagonists1.
Year : 1999
Volume : 42
Issue : 3
First Page : 356
Last Page : 363
Authors : Augelli-Szafran CE, Blankley CJ, Jaen JC, Moreland DW, Nelson CB, Penvose-Yi JR, Schwarz RD, Thomas AJ.
Abstract : A series of esters of 1,4-disubstituted tetrahydropyridine carboxylic acids (I) has been synthesized and characterized as potential m1 selective muscarinic receptor antagonists. The affinity of these compounds for the five human muscarinic receptor subtypes (Hm1-Hm5) was determined by the displacement of [3H]-NMS binding using membranes from transfected Chinese hamster ovarian cells. One of the most potent and selective compounds of this series is an analogue of I [11, R1 = (CH2)5CH3], which has an IC50 value of 27.3 nM at the m1 receptor and possesses 100-fold (m2), 48-fold (m3), 74-fold (m4), and 19-fold (m5) selectivities at the other receptors. Thus, this analogue appears to be more selective on the basis of binding than the prototypical m1 antagonist, pirenzepine. Functional data, such as the inhibition of carbachol-stimulated phosphatidylinositol hydrolysis, on selected analogues confirmed the muscarinic antagonistic properties of this chemical series.
|
Binding affinity for muscarinic acetylcholine receptor M3 by measuring displacement of [3H]QNB from guinea pig parotid gland
|
Cavia porcellus
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-Heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives as muscarinic antagonists. Synthesis and structure-activity relationships.
Year : 1995
Volume : 38
Issue : 3
First Page : 473
Last Page : 487
Authors : Nilsson BM, Sundquist S, Johansson G, Nordvall G, Glas G, Nilvebrant L, Hacksell U.
Abstract : A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for muscarinic and antimuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate [(-)-[3H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive muscarinic antagonists in the urinary bladder. The highest receptor binding affinity, Ki (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3-benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antimuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the muscarinic m1 receptor.
|
Binding affinity for muscarinic acetylcholine receptor by measuring displacement of [3H]QNB from guinea pig urinary bladder
|
Cavia porcellus
|
530.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-Heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives as muscarinic antagonists. Synthesis and structure-activity relationships.
Year : 1995
Volume : 38
Issue : 3
First Page : 473
Last Page : 487
Authors : Nilsson BM, Sundquist S, Johansson G, Nordvall G, Glas G, Nilvebrant L, Hacksell U.
Abstract : A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for muscarinic and antimuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate [(-)-[3H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive muscarinic antagonists in the urinary bladder. The highest receptor binding affinity, Ki (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3-benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antimuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the muscarinic m1 receptor.
|
Displacement of [3H]-NMS binding to human Muscarinic acetylcholine receptor M3 using membranes from transfected CHO cells
|
None
|
955.6
nM
|
|
Journal : J. Med. Chem.
Title : Identification and characterization of m1 selective muscarinic receptor antagonists1.
Year : 1999
Volume : 42
Issue : 3
First Page : 356
Last Page : 363
Authors : Augelli-Szafran CE, Blankley CJ, Jaen JC, Moreland DW, Nelson CB, Penvose-Yi JR, Schwarz RD, Thomas AJ.
Abstract : A series of esters of 1,4-disubstituted tetrahydropyridine carboxylic acids (I) has been synthesized and characterized as potential m1 selective muscarinic receptor antagonists. The affinity of these compounds for the five human muscarinic receptor subtypes (Hm1-Hm5) was determined by the displacement of [3H]-NMS binding using membranes from transfected Chinese hamster ovarian cells. One of the most potent and selective compounds of this series is an analogue of I [11, R1 = (CH2)5CH3], which has an IC50 value of 27.3 nM at the m1 receptor and possesses 100-fold (m2), 48-fold (m3), 74-fold (m4), and 19-fold (m5) selectivities at the other receptors. Thus, this analogue appears to be more selective on the basis of binding than the prototypical m1 antagonist, pirenzepine. Functional data, such as the inhibition of carbachol-stimulated phosphatidylinositol hydrolysis, on selected analogues confirmed the muscarinic antagonistic properties of this chemical series.
|
Ability (10 ug/kg) to inhibit binding of [125I]iododexetimide to muscarinic receptor in mice
|
None
|
750.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of [125I]- and [123I]-4-iododexetimide, a potent muscarinic cholinergic receptor antagonist.
Year : 1989
Volume : 32
Issue : 5
First Page : 1057
Last Page : 1062
Authors : Wilson AA, Dannals RF, Ravert HT, Frost JJ, Wagner HN.
Abstract : A series of halogenated racemic analogues of dexetimide (1) was synthesized and their affinity for the muscarinic cholinergic receptor measured. One analogue, 4-iododexetimide (21), was efficiently labeled with 125I and 123I at high specific activity. In vitro binding studies and in vivo biodistribution studies suggest that 123I-labeled 21 may be useful for imaging muscarinic cholinergic receptors in the living human brain with single photon emission computed tomography.
|
Binding affinity towards Muscarinic acetylcholine receptor M1 of cerebral cortex
|
None
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic compounds as selective antimuscarinics. 2. Structure-activity relationships of M1-selective antimuscarinics related to pirenzepine.
Year : 1988
Volume : 31
Issue : 6
First Page : 1169
Last Page : 1174
Authors : Eberlein WG, Engel WW, Trummlitz G, Schmidt G, Hammer R.
Abstract : In order to gain some insight into those structural features that control M1 selectivity, a selected set of pirenzepine analogues has been studied in which both the tricyclic ring system and the basic side chain have been varied. Binding studies were conducted in rat tissue homogenates from cerebral cortex (M1) and gastric fundus (M2). The ratio of IC50 values of the test compounds in the two different tissues was taken as a measure of M1 receptor selectivity. Several derivatives, especially those with flexible side chains, i.e. high degree of freedom of rotation around single bonds, proved to be nonselective. Among semirigid compounds only those containing 6-membered ring systems (11, 13, 14, and 15) showed significant M1 selectivity. Principles of structure-activity and structure-selectivity are discussed.
|
In vitro ability to displace [3H]oxotremorine-M (OXO-M) from rat cerebral cortex muscarinic receptor.
|
None
|
322.0
nM
|
|
Journal : J. Med. Chem.
Title : Substituent variation in azabicyclic triazole- and tetrazole-based muscarinic receptor ligands.
Year : 1992
Volume : 35
Issue : 13
First Page : 2392
Last Page : 2406
Authors : Jenkins SM, Wadsworth HJ, Bromidge S, Orlek BS, Wyman PA, Riley GJ, Hawkins J.
Abstract : The effect of variation of the 1-azabicyclic substituent on the novel 1,2,3-triazol-4-yl-, 1,2,4-triazol-1-yl, tetrazol-5-yl-, and tetrazol-2-yl-based muscarinic receptor ligands has been studied, and the exo-azabicyclic[2.2.1]hept-3-yl substituent was found to give the most potent and efficacious compounds. In addition, variation of the second substituent on 1,2,4-triazol-1-yl- and tetrazol-2-yl-based muscarinic receptor ligands has yielded a series of novel compounds with high potencies and efficacies, ranging from full agonists to antagonists. Small lipophilic electron withdrawing substituents give potent but low efficacy compounds, while small polar electron donating substituents give potent and efficacious compounds. The activity of these compounds is described in terms of a model of the receptor involving lipophilic and hydrogen bonding interactions. These compounds provide muscarinic ligands with high potency and a range of efficacies suitable for testing as candidate drugs in the treatment of Alzheimer's disease.
|
In vitro displacement of [3H]quinuclidinyl benzilate (QNB) from rat cerebral cortex muscarinic receptor.
|
None
|
213.0
nM
|
|
Journal : J. Med. Chem.
Title : Substituent variation in azabicyclic triazole- and tetrazole-based muscarinic receptor ligands.
Year : 1992
Volume : 35
Issue : 13
First Page : 2392
Last Page : 2406
Authors : Jenkins SM, Wadsworth HJ, Bromidge S, Orlek BS, Wyman PA, Riley GJ, Hawkins J.
Abstract : The effect of variation of the 1-azabicyclic substituent on the novel 1,2,3-triazol-4-yl-, 1,2,4-triazol-1-yl, tetrazol-5-yl-, and tetrazol-2-yl-based muscarinic receptor ligands has been studied, and the exo-azabicyclic[2.2.1]hept-3-yl substituent was found to give the most potent and efficacious compounds. In addition, variation of the second substituent on 1,2,4-triazol-1-yl- and tetrazol-2-yl-based muscarinic receptor ligands has yielded a series of novel compounds with high potencies and efficacies, ranging from full agonists to antagonists. Small lipophilic electron withdrawing substituents give potent but low efficacy compounds, while small polar electron donating substituents give potent and efficacious compounds. The activity of these compounds is described in terms of a model of the receptor involving lipophilic and hydrogen bonding interactions. These compounds provide muscarinic ligands with high potency and a range of efficacies suitable for testing as candidate drugs in the treatment of Alzheimer's disease.
|
In vitro inhibition of [3H]OXO-M binding to Muscarinic receptor from rat cortical homogenates
|
Rattus norvegicus
|
322.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives.
Year : 1992
Volume : 35
Issue : 7
First Page : 1280
Last Page : 1290
Authors : Wadsworth HJ, Jenkins SM, Orlek BS, Cassidy F, Clark MS, Brown F, Riley GJ, Graves D, Hawkins J, Naylor CB.
Abstract : The synthesis of 15 methyl or unsubstituted 1,2,3-triazoles, 1,2,4-triazoles, and tetrazoles additionally substituted with a 1-azabicyclo[2.2.2]octan-3-yl group is described. The potency and efficacy of these compounds as muscarinic ligands were determined in radioligand binding assays using [3H]oxotremorine and [3H]quinuclidinyl benzilate. Potency and efficacy were found in compounds in which the azole moiety was attached to the azabicyclic ring either through a carbon atom or a nitrogen atom. Electrostatic potential maps of both the C-linked and the novel N-linked series of compounds were calculated. A relationship between position and depth of the electrostatic minima relative to the azabicyclic ring and the potency and efficacy of the compounds was determined.
|
In vitro inhibition of [3H]QNB binding to Muscarinic receptor from rat cortical homogenates
|
Rattus norvegicus
|
213.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives.
Year : 1992
Volume : 35
Issue : 7
First Page : 1280
Last Page : 1290
Authors : Wadsworth HJ, Jenkins SM, Orlek BS, Cassidy F, Clark MS, Brown F, Riley GJ, Graves D, Hawkins J, Naylor CB.
Abstract : The synthesis of 15 methyl or unsubstituted 1,2,3-triazoles, 1,2,4-triazoles, and tetrazoles additionally substituted with a 1-azabicyclo[2.2.2]octan-3-yl group is described. The potency and efficacy of these compounds as muscarinic ligands were determined in radioligand binding assays using [3H]oxotremorine and [3H]quinuclidinyl benzilate. Potency and efficacy were found in compounds in which the azole moiety was attached to the azabicyclic ring either through a carbon atom or a nitrogen atom. Electrostatic potential maps of both the C-linked and the novel N-linked series of compounds were calculated. A relationship between position and depth of the electrostatic minima relative to the azabicyclic ring and the potency and efficacy of the compounds was determined.
|
Binding affinity for glandular muscarinic acetylcholine receptor M3 in rat assayed using 0.3 nM [3H]N-methylscopolamine as radioligand
|
None
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic compounds as selective muscarinic receptor antagonists. 3. Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics.
Year : 1989
Volume : 32
Issue : 8
First Page : 1718
Last Page : 1724
Authors : Engel WW, Eberlein WG, Mihm G, Hammer R, Trummlitz G.
Abstract : On the basis of the cardioselective muscarinic receptor antagonist AF-DX 116 (2), a series of 11-substituted pyridobenzodiazepinones (9-35) was prepared and screened for their binding affinity to muscarinic receptors located in cardiac (M2) and glandular (M3) tissue. The ratio of IC50 values of the test compounds in the two different tissues was taken as a measure of cardiac (M2) receptor selectivity. Qualitative structure-selectivity relationships point to the fact that it is the spatial orientation of the protonated side-chain nitrogen atom in relation to the tricycle that is the main determinant for receptor subtype recognition and hence is important for the achievement of cardiac (M2) selectivity.
|
Inhibition of binding of [3H]N-methylscopolamine to muscarinic acetylcholine receptor M3 of transfected rat A9L cells.
|
None
|
240.0
nM
|
|
Journal : J. Med. Chem.
Title : Functionalized congener approach to muscarinic antagonists: analogues of pirenzepine.
Year : 1991
Volume : 34
Issue : 7
First Page : 2133
Last Page : 2145
Authors : Karton Y, Bradbury BJ, Baumgold J, Paek R, Jacobson KA.
Abstract : The M1-selective muscarinic receptor antagonist pirenzepine 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one) was derivatized to explore points of attachment of functionalized side chains for the synthesis of receptor probes and ligands for affinity chromatography. The analogues prepared were evaluated in competitive binding assays versus [3H]-N-methylscopolamine at four muscarinic receptor subtypes (m1AChR-m4AChR) in membranes from rat heart tissue and transfected A9L cells. 9-(Hydroxymethyl)pirenzepine, 8-(methylthio)pirenzepine, and a series of 8-aminosulfonyl derivatives were synthesized. Several 5-substituted analogues of pirenzepine also were prepared. An alternate series of analogues substituted on the 4-position of the piperazine ring was prepared by reaction of 4-desmethylpirenzepine with various electrophiles. An N-chloroethyl analogue of pirenzepine was shown to form a reactive aziridine species in aqueous buffer yet failed to affinity label muscarinic receptors. Within a series of aminoalkyl analogues, the affinity increased as the length of the alkyl chain increased. Shorter chain analogues were generally much less potent than pirenzepine, and longer analogues (7-10 carbons) were roughly as potent as pirenzepine at m1 receptors, but were nonselective. Depending on the methylene chain length, acylation or alkyl substitution of the terminal amine also influenced the affinity at muscarinic receptors.
|
Displacement of [3H]pirenzepine from muscarinic acetylcholine receptor M1 in rat cortex homogenates
|
Rattus norvegicus
|
5.21
nM
|
|
Journal : J. Med. Chem.
Title : Muscarinic receptor binding profile of para-substituted caramiphen analogues.
Year : 1991
Volume : 34
Issue : 10
First Page : 2984
Last Page : 2989
Authors : Hudkins RL, DeHaven-Hudkins DL, Stubbins JF.
Abstract : Para-substituted analogues of the antimuscarinic agent caramiphen were synthesized and evaluated for their ability to bind to the M1 and M2 subtypes of the muscarinic receptor. The purpose of the set was to look for a possible relationship in binding affinity or receptor subtype selectivity with aromatic substituent parameters such as Hammett's sigma or Hansch's pi values. It is felt this could be determined initially with only four properly chosen substituents. In this approach, substituents were chosen which have an extreme value for sigma and for pi, in a positive and negative direction, in all combinations. The substituents chosen for examination were amino (-sigma, -pi); 1-pyrrolidinyl (-sigma, +pi); 1-tetrazolyl (+sigma, -pi), and iodo (+sigma, +pi). It was determined in this research that caramiphen binds with high affinity (Ki = 1.2 nM) and is selective for the M1 over M2 muscarinic receptor subtype (26-fold). An examination of para-substitution reveals that compounds with electron-withdrawing (+sigma) substituents showed M1 selectivity, while the derivatives with electron-donating groups (-sigma) were nonselective in the binding assays. On the basis of this finding, the nitro and cyano derivatives were prepared and found to be M1 selective. The + sigma derivatives showed a decrease in M2 affinity while the p-nitro and p-iodo derivatives retained approximately equal affinity as caramiphen for the M1 site. The nitro- and iodocaramiphen derivatives were as potent (M1, Ki = 5.52 and 2.11 nM, respectively) and showed a greater selectivity of M1 over M2 binding than the M1 prototypical agent pirenzepine (M1, Ki = 5.21 nM).
|
Inhibition of binding of [3H]N-methylscopolamine to muscarinic acetylcholine receptor M1 of transfected rat A9L cells.
|
None
|
29.0
nM
|
|
Journal : J. Med. Chem.
Title : Functionalized congener approach to muscarinic antagonists: analogues of pirenzepine.
Year : 1991
Volume : 34
Issue : 7
First Page : 2133
Last Page : 2145
Authors : Karton Y, Bradbury BJ, Baumgold J, Paek R, Jacobson KA.
Abstract : The M1-selective muscarinic receptor antagonist pirenzepine 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one) was derivatized to explore points of attachment of functionalized side chains for the synthesis of receptor probes and ligands for affinity chromatography. The analogues prepared were evaluated in competitive binding assays versus [3H]-N-methylscopolamine at four muscarinic receptor subtypes (m1AChR-m4AChR) in membranes from rat heart tissue and transfected A9L cells. 9-(Hydroxymethyl)pirenzepine, 8-(methylthio)pirenzepine, and a series of 8-aminosulfonyl derivatives were synthesized. Several 5-substituted analogues of pirenzepine also were prepared. An alternate series of analogues substituted on the 4-position of the piperazine ring was prepared by reaction of 4-desmethylpirenzepine with various electrophiles. An N-chloroethyl analogue of pirenzepine was shown to form a reactive aziridine species in aqueous buffer yet failed to affinity label muscarinic receptors. Within a series of aminoalkyl analogues, the affinity increased as the length of the alkyl chain increased. Shorter chain analogues were generally much less potent than pirenzepine, and longer analogues (7-10 carbons) were roughly as potent as pirenzepine at m1 receptors, but were nonselective. Depending on the methylene chain length, acylation or alkyl substitution of the terminal amine also influenced the affinity at muscarinic receptors.
|
Displacement of [3H]NMS binding to human Muscarinic acetylcholine receptor M4 using membranes from transfected CHO cells
|
None
|
246.8
nM
|
|
Journal : J. Med. Chem.
Title : Identification and characterization of m1 selective muscarinic receptor antagonists1.
Year : 1999
Volume : 42
Issue : 3
First Page : 356
Last Page : 363
Authors : Augelli-Szafran CE, Blankley CJ, Jaen JC, Moreland DW, Nelson CB, Penvose-Yi JR, Schwarz RD, Thomas AJ.
Abstract : A series of esters of 1,4-disubstituted tetrahydropyridine carboxylic acids (I) has been synthesized and characterized as potential m1 selective muscarinic receptor antagonists. The affinity of these compounds for the five human muscarinic receptor subtypes (Hm1-Hm5) was determined by the displacement of [3H]-NMS binding using membranes from transfected Chinese hamster ovarian cells. One of the most potent and selective compounds of this series is an analogue of I [11, R1 = (CH2)5CH3], which has an IC50 value of 27.3 nM at the m1 receptor and possesses 100-fold (m2), 48-fold (m3), 74-fold (m4), and 19-fold (m5) selectivities at the other receptors. Thus, this analogue appears to be more selective on the basis of binding than the prototypical m1 antagonist, pirenzepine. Functional data, such as the inhibition of carbachol-stimulated phosphatidylinositol hydrolysis, on selected analogues confirmed the muscarinic antagonistic properties of this chemical series.
|
Percentage inhibition for muscarinic acetylcholine receptor at concentration 10 e-5M.
|
None
|
83.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiulcer activity of 5,11-dihydro[1]benzoxepino[3,4-b]pyridines.
Year : 1988
Volume : 31
Issue : 4
First Page : 779
Last Page : 785
Authors : Kumazawa T, Harakawa H, Obase H, Oiji Y, Tanaka H, Shuto K, Ishii A, Oka T, Nakamizo N.
Abstract : A series of substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines was synthesized and evaluated for antiulcer activity in water immersion/restrained stress ulcer assay in rats. Structure-activity relationships are described. Most of the tested compounds exhibited low affinity to the muscarinic acetylcholine receptor. The molecular features for the best activities are the 2-(diethylamino)ethylenediamine group at the 5-position of the oxepin ring and an oxepin skeleton rather than a thiepin or a pyran skeleton. Methyl and chlorine substitution on the benzene ring reduced the activity. Compound 11, 5-[[2-(diethylamino)ethyl]amino]-5,11-dihydro[1]benzoxepino [3,4-b]pyridine trihydrochloride was selected for further evaluation. Synthesis and antiulcer activity of optically active 11 is described. There were no statistically significant differences between (+)-, (-)-, and (+/-)-11. Compound 11 showed weak antisecretory activity in pylorus-ligated rats. It is now under clinical evaluation as KW 5805.
|
Percentage inhibition for muscarinic acetylcholine receptor at concentration 10e-6 M.
|
None
|
38.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiulcer activity of 5,11-dihydro[1]benzoxepino[3,4-b]pyridines.
Year : 1988
Volume : 31
Issue : 4
First Page : 779
Last Page : 785
Authors : Kumazawa T, Harakawa H, Obase H, Oiji Y, Tanaka H, Shuto K, Ishii A, Oka T, Nakamizo N.
Abstract : A series of substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines was synthesized and evaluated for antiulcer activity in water immersion/restrained stress ulcer assay in rats. Structure-activity relationships are described. Most of the tested compounds exhibited low affinity to the muscarinic acetylcholine receptor. The molecular features for the best activities are the 2-(diethylamino)ethylenediamine group at the 5-position of the oxepin ring and an oxepin skeleton rather than a thiepin or a pyran skeleton. Methyl and chlorine substitution on the benzene ring reduced the activity. Compound 11, 5-[[2-(diethylamino)ethyl]amino]-5,11-dihydro[1]benzoxepino [3,4-b]pyridine trihydrochloride was selected for further evaluation. Synthesis and antiulcer activity of optically active 11 is described. There were no statistically significant differences between (+)-, (-)-, and (+/-)-11. Compound 11 showed weak antisecretory activity in pylorus-ligated rats. It is now under clinical evaluation as KW 5805.
|
Inhibition of binding of [3H]N-Methyl-scopolamine to muscarinic acetylcholine receptor M4 of rat heart NG108-15 cells
|
None
|
330.0
nM
|
|
Journal : J. Med. Chem.
Title : Functionalized congener approach to muscarinic antagonists: analogues of pirenzepine.
Year : 1991
Volume : 34
Issue : 7
First Page : 2133
Last Page : 2145
Authors : Karton Y, Bradbury BJ, Baumgold J, Paek R, Jacobson KA.
Abstract : The M1-selective muscarinic receptor antagonist pirenzepine 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one) was derivatized to explore points of attachment of functionalized side chains for the synthesis of receptor probes and ligands for affinity chromatography. The analogues prepared were evaluated in competitive binding assays versus [3H]-N-methylscopolamine at four muscarinic receptor subtypes (m1AChR-m4AChR) in membranes from rat heart tissue and transfected A9L cells. 9-(Hydroxymethyl)pirenzepine, 8-(methylthio)pirenzepine, and a series of 8-aminosulfonyl derivatives were synthesized. Several 5-substituted analogues of pirenzepine also were prepared. An alternate series of analogues substituted on the 4-position of the piperazine ring was prepared by reaction of 4-desmethylpirenzepine with various electrophiles. An N-chloroethyl analogue of pirenzepine was shown to form a reactive aziridine species in aqueous buffer yet failed to affinity label muscarinic receptors. Within a series of aminoalkyl analogues, the affinity increased as the length of the alkyl chain increased. Shorter chain analogues were generally much less potent than pirenzepine, and longer analogues (7-10 carbons) were roughly as potent as pirenzepine at m1 receptors, but were nonselective. Depending on the methylene chain length, acylation or alkyl substitution of the terminal amine also influenced the affinity at muscarinic receptors.
|
Inhibition of binding of [3H]N-methylscopolamine to Muscarinic acetylcholine receptor M4 in NG 108-15 cell homogenates
|
None
|
34.67
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological activity of some tetraamines related to methoctramine and 4-DAMP
Year : 1995
Volume : 5
Issue : 8
First Page : 785
Last Page : 790
Authors : Melchiorre C, Minarini A, Spampinato S, Tumiatti V
|
Compound was tested for inhibiting [3H]N-Methyl-scopolamine Binding to Muscarinic acetylcholine receptor M4 in NG 108-15 Cell
|
None
|
34.67
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological activity of some 4-DAMP- related compounds
Year : 1995
Volume : 5
Issue : 20
First Page : 2325
Last Page : 2330
Authors : Tumiatti V, Santi S, Recanatini M, Minarini A, Melchiorre C, Chiarini A, Budriesi R
|
Binding affinity for muscarinic acetylcholine receptor M2 by measuring displacement of [3H]QNB from guinea pig heart
|
Cavia porcellus
|
270.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-Heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives as muscarinic antagonists. Synthesis and structure-activity relationships.
Year : 1995
Volume : 38
Issue : 3
First Page : 473
Last Page : 487
Authors : Nilsson BM, Sundquist S, Johansson G, Nordvall G, Glas G, Nilvebrant L, Hacksell U.
Abstract : A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for muscarinic and antimuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate [(-)-[3H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive muscarinic antagonists in the urinary bladder. The highest receptor binding affinity, Ki (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3-benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antimuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the muscarinic m1 receptor.
|
Displacement of [3H]NMS binding to human Muscarinic acetylcholine receptor M5 using membranes from transfected CHO cells
|
None
|
340.6
nM
|
|
Journal : J. Med. Chem.
Title : Identification and characterization of m1 selective muscarinic receptor antagonists1.
Year : 1999
Volume : 42
Issue : 3
First Page : 356
Last Page : 363
Authors : Augelli-Szafran CE, Blankley CJ, Jaen JC, Moreland DW, Nelson CB, Penvose-Yi JR, Schwarz RD, Thomas AJ.
Abstract : A series of esters of 1,4-disubstituted tetrahydropyridine carboxylic acids (I) has been synthesized and characterized as potential m1 selective muscarinic receptor antagonists. The affinity of these compounds for the five human muscarinic receptor subtypes (Hm1-Hm5) was determined by the displacement of [3H]-NMS binding using membranes from transfected Chinese hamster ovarian cells. One of the most potent and selective compounds of this series is an analogue of I [11, R1 = (CH2)5CH3], which has an IC50 value of 27.3 nM at the m1 receptor and possesses 100-fold (m2), 48-fold (m3), 74-fold (m4), and 19-fold (m5) selectivities at the other receptors. Thus, this analogue appears to be more selective on the basis of binding than the prototypical m1 antagonist, pirenzepine. Functional data, such as the inhibition of carbachol-stimulated phosphatidylinositol hydrolysis, on selected analogues confirmed the muscarinic antagonistic properties of this chemical series.
|
Binding affinity against Muscarinic acetylcholine receptor was determined in homogenized rat cortex tissue using [3H]N-methylscopolamine as radioligand
|
None
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic compounds as selective antimuscarinics. 1. Structural requirements for selectivity toward the muscarinic acetylcholine receptor in a series of pirenzepine and imipramine analogues.
Year : 1987
Volume : 30
Issue : 8
First Page : 1378
Last Page : 1382
Authors : Eberlein WG, Trummlitz G, Engel WW, Schmidt G, Pelzer H, Mayer N.
Abstract : The M1-selective antiulcer drug pirenzepine (1) is a tricyclic compound with close resemblance to tricyclic psychotropic agents such as imipramine (2). Despite this fact, pirenzepine is devoid of any psychotropic effects, exhibiting measurable antagonistic effects in biochemical assays and receptor binding studies only toward the muscarinic receptor system. To understand how different groups in these tricyclic molecules affect binding affinities, a set of nine compounds structurally related to pirenzepine (1) and imipramine (2) has been selected for analysis, comprising three different tricycles and three different side chains. The compounds were tested for their affinity to the imipramine and muscarinic receptors in homogenized rat cortex tissue. The result of these studies suggests that it is the nature and placement of accessory groups that determine the differences in receptor recognition and the binding process. In the case of pirenzepine (1), preferential binding toward the muscarinic receptor is brought about by the endocyclic amide group, by the positioning of the protonated N atom of the side chain, and to a minor extent by the exocyclic amide group. From these findings a putative model for the explanation of selective binding of pirenzepine (1) to the muscarinic receptor has been derived.
|
Compound was tested for its binding affinity against M1 human recombinant muscarinic receptor in CHO cells.
|
None
|
119.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Binding affinities of 3-(3-phenylisoxazol-5-yl)methylidene-1-azabicycles to acetylcholine receptors.
Year : 1999
Volume : 9
Issue : 19
First Page : 2795
Last Page : 2800
Authors : Choi KI, Cha JH, Cho YS, Pae AN, Jin C, Yook J, Cheon HG, Jeong D, Kong JY, Koh HY.
Abstract : A series of 3-(3-phenylisoxazol-5-yl)methylidene-1-azabicycles synthesized showed different binding characteristics to acetylcholine receptors depending on the substituents on the phenyl ring. Small polar substituents gave preferential binding affinity to nicotinic receptors, and large hydrophobic substituents to muscarinic receptors.
|
Compound was evaluated for displacement of [3H]QNB from human Muscarinic m1 receptor in CHO cells.
|
None
|
4.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The N4 nitrogen of pirenzepine is responsible for selective binding of the M1 subtype human muscarinic receptor
Year : 1996
Volume : 6
Issue : 7
First Page : 785
Last Page : 788
Authors : Murgolo NJ, Kozlowski J, Tice MA, Hollinger FP, Brown JE, Zhou G, Taylor LA, McQuade RD
|
Displacement of [3H]NMS binding to human Muscarinic acetylcholine receptor M2 using membranes from transfected CHO cells
|
None
|
968.2
nM
|
|
Journal : J. Med. Chem.
Title : Identification and characterization of m1 selective muscarinic receptor antagonists1.
Year : 1999
Volume : 42
Issue : 3
First Page : 356
Last Page : 363
Authors : Augelli-Szafran CE, Blankley CJ, Jaen JC, Moreland DW, Nelson CB, Penvose-Yi JR, Schwarz RD, Thomas AJ.
Abstract : A series of esters of 1,4-disubstituted tetrahydropyridine carboxylic acids (I) has been synthesized and characterized as potential m1 selective muscarinic receptor antagonists. The affinity of these compounds for the five human muscarinic receptor subtypes (Hm1-Hm5) was determined by the displacement of [3H]-NMS binding using membranes from transfected Chinese hamster ovarian cells. One of the most potent and selective compounds of this series is an analogue of I [11, R1 = (CH2)5CH3], which has an IC50 value of 27.3 nM at the m1 receptor and possesses 100-fold (m2), 48-fold (m3), 74-fold (m4), and 19-fold (m5) selectivities at the other receptors. Thus, this analogue appears to be more selective on the basis of binding than the prototypical m1 antagonist, pirenzepine. Functional data, such as the inhibition of carbachol-stimulated phosphatidylinositol hydrolysis, on selected analogues confirmed the muscarinic antagonistic properties of this chemical series.
|
Compound was evaluated for displacement of [3H]-QNB from human Muscarinic m2 receptor in CHO cells.
|
None
|
251.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The N4 nitrogen of pirenzepine is responsible for selective binding of the M1 subtype human muscarinic receptor
Year : 1996
Volume : 6
Issue : 7
First Page : 785
Last Page : 788
Authors : Murgolo NJ, Kozlowski J, Tice MA, Hollinger FP, Brown JE, Zhou G, Taylor LA, McQuade RD
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of Primary olfactory cortex region of forebrain
|
Rattus norvegicus
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of anterior cingulate cortex region of forebrain
|
Rattus norvegicus
|
710.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of basolateral amygdaloid nucleus region of forebrain
|
Rattus norvegicus
|
450.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of bed nucleus stria terminalis region of midbrain
|
Rattus norvegicus
|
440.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of central amygdaloid nucleus region of forebrain
|
Rattus norvegicus
|
430.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of central gray, pons region of hindbrain
|
Rattus norvegicus
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of cerebellum, lobe 1 region of hindbrain
|
Rattus norvegicus
|
900.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of cerebellum, lobe 2 region of hindbrain
|
Rattus norvegicus
|
740.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of cerebellum, lobe 3 region of hindbrain
|
Rattus norvegicus
|
900.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of cerebellum, lobe 4 region of hindbrain
|
Rattus norvegicus
|
840.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of cerebral cortex layers I-III of forebrain
|
Rattus norvegicus
|
440.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of cerebral cortex layers IV and V of forebrain
|
Rattus norvegicus
|
480.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of cerebral cortex layers VI of forebrain
|
Rattus norvegicus
|
520.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of cudate nucleus region of forebrain
|
Rattus norvegicus
|
310.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of cuneiform nucleus region of hindbrain
|
Rattus norvegicus
|
850.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of dentate gyrus region of forebrain
|
Rattus norvegicus
|
190.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of dorsal lateral geniculate region of midbrain
|
Rattus norvegicus
|
480.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of dorsal parabrachial nucleus region of hindbrain
|
Rattus norvegicus
|
550.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of dorsal tegmentum region of hindbrain
|
Rattus norvegicus
|
650.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of entorhinal cortex region of forebrain
|
Rattus norvegicus
|
240.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Displacement of [3H]pirenzepine binding to muscarinic M1 receptor in brain cortex of rat.
|
None
|
3.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Quinolizidinyl derivatives of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one as ligands for muscarinic receptors.
Year : 1999
Volume : 9
Issue : 20
First Page : 3031
Last Page : 3034
Authors : Novelli F, Sparatore A, Tasso B, Sparatore F.
Abstract : Quinolizidinyl derivatives of the tricyclic systems characterizing pirenzepine and nuvenzepine, were prepared and tested as ligands for muscarinic M1, M2 and M3 receptors; 5,11-dihydro-11-[(S-lupinyl)-thioacetyl]-6H-pyrido[2,3-b][1, 4]benzodiazepin-6-one exhibited IC50 = 10 nM for M1 and 760 nM for both M2 and M3 subtypes. During the synthesis some interesting side compounds were isolated and characterized.
|
Displacement of [3H]pirenzepine from muscarinic M1 receptor of rat cortex homogenates.
|
Rattus norvegicus
|
5.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design of dual acting anticonvulsant-antimuscarinic succinimide and hydantoin derivatives
Year : 1997
Volume : 7
Issue : 8
First Page : 979
Last Page : 984
Authors : Hudkins RL, DeHaven-Hudkins DL, Doukas P
|
Tested for affinity constant against M1 muscarinic receptor in rat cortex using [3H]pirenzepine
|
None
|
6.457
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological activity of methoctramine-related tetraamines bearing an 11-acetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one moiety: structural requirements for optimum occupancy of muscarinic receptor subtypes as revealed by symmetrical and unsymmetrical polyamines.
Year : 1994
Volume : 37
Issue : 20
First Page : 3363
Last Page : 3372
Authors : Minarini A, Bolognesi ML, Budriesi R, Canossa M, Chiarini A, Spampinato S, Melchiorre C.
Abstract : Tetraamines 5-13 and diamines 14-17 as well as monoamine 18 were synthesized, and their biological profiles at muscarinic receptor subtypes were assessed by functional experiments in isolated guinea pig left atrium (M2) and ileum (M3) and by binding assays in rat cortex (M1), heart (M2), and submaxillary gland (M3) homogenates and NG 108-15 cells (M4). An appropriate number and type of substituents on the terminal nitrogens of a tetraamine backbone afforded compounds, such as tripitramine (8) and dipitramine (6), which are endowed with different affinity and selectivity profiles. Tripitramine, a nonsymmetrical tetraamine, resulted in the most potent and the most selective M2 muscarinic receptor antagonist so far available (pA2 = 9.75 +/- 0.02; pKi = 9.54 +/- 0.08). However, it failed to discriminate between M1 and M4 muscarinic receptor subtypes (selectivity ratio: M2/M3, 1600-2200; M2/M1, 81; M2/M4, 41; M1/M3, 28; M4/M3, 55; M4/M1, 2). Dipitramine, another nonsymmetrical tetraamine bearing two substituents on the same terminal nitrogen, displayed the highest affinity for M1 muscarinic receptors (pKi = 8.60 +/- 0.15) and was able to differentiate, unlike 8, all four muscarinic receptor subtypes investigated (selectivity ratio: M1/M2, 5; M1/M3, 2700; M1/M4, 76; M2/M3, 260-520; M2/M4, 15; M4/M3, 35). The results are discussed in terms of a possible mode of interaction of tetraamines with muscarinic receptor subtypes.
|
Compound was tested for inhibiting [3H]pirenzepine Binding to Muscarinic receptor (M1) receptor in Rat Cortex Homogenates
|
None
|
6.457
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological activity of some 4-DAMP- related compounds
Year : 1995
Volume : 5
Issue : 20
First Page : 2325
Last Page : 2330
Authors : Tumiatti V, Santi S, Recanatini M, Minarini A, Melchiorre C, Chiarini A, Budriesi R
|
Inhibition of binding of [3H]pirenzepine to muscarinic receptor (M1) in rat cortex homogenates
|
None
|
6.457
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological activity of some tetraamines related to methoctramine and 4-DAMP
Year : 1995
Volume : 5
Issue : 8
First Page : 785
Last Page : 790
Authors : Melchiorre C, Minarini A, Spampinato S, Tumiatti V
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of hippocampus CA1 region of forebrain
|
Rattus norvegicus
|
290.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of hippocampus CA3 region of forebrain
|
Rattus norvegicus
|
270.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of hippocampus CA4 region of forebrain
|
Rattus norvegicus
|
290.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of inferior coliculus region of hindbrain
|
Rattus norvegicus
|
570.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of lateral amygdaloid nucleus region of forebrain
|
Rattus norvegicus
|
330.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of lateral septal nucleus of midbrain
|
Rattus norvegicus
|
710.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of lateral hypothalamus region of midbrain
|
Rattus norvegicus
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of medial amygdaloid nucleus region of forebrain
|
Rattus norvegicus
|
230.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of medial dorsal thalamic nucleus region of midbrain
|
Rattus norvegicus
|
680.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of medial geniculate region of midbrain
|
Rattus norvegicus
|
540.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of medial raphe nucleus region of hindbrain
|
Rattus norvegicus
|
820.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of neostriatum region of forebrain
|
Rattus norvegicus
|
790.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of posterior cingulate cortex region of forebrain
|
Rattus norvegicus
|
790.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of posterior thalamic nucleus region of midbrain
|
Rattus norvegicus
|
850.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of raphe pontis region of hindbrain
|
Rattus norvegicus
|
450.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of reticular thalamic nucleus region of midbrain
|
Rattus norvegicus
|
610.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of retrosplenial cortex region of forebrain
|
Rattus norvegicus
|
460.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of subiculum region of forebrain
|
Rattus norvegicus
|
410.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of substantia nigra region of midbrain
|
Rattus norvegicus
|
270.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Binding affinity to the rat cardiac muscarinic acetylcholine receptor M2 using 0.3 nM [3H]N-methylscopolamine as radioligand
|
None
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic compounds as selective muscarinic receptor antagonists. 3. Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics.
Year : 1989
Volume : 32
Issue : 8
First Page : 1718
Last Page : 1724
Authors : Engel WW, Eberlein WG, Mihm G, Hammer R, Trummlitz G.
Abstract : On the basis of the cardioselective muscarinic receptor antagonist AF-DX 116 (2), a series of 11-substituted pyridobenzodiazepinones (9-35) was prepared and screened for their binding affinity to muscarinic receptors located in cardiac (M2) and glandular (M3) tissue. The ratio of IC50 values of the test compounds in the two different tissues was taken as a measure of cardiac (M2) receptor selectivity. Qualitative structure-selectivity relationships point to the fact that it is the spatial orientation of the protonated side-chain nitrogen atom in relation to the tricycle that is the main determinant for receptor subtype recognition and hence is important for the achievement of cardiac (M2) selectivity.
|
Displacement of [3H]methylscopolamine binding to muscarinic M2 receptor in rat heart.
|
None
|
690.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Quinolizidinyl derivatives of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one as ligands for muscarinic receptors.
Year : 1999
Volume : 9
Issue : 20
First Page : 3031
Last Page : 3034
Authors : Novelli F, Sparatore A, Tasso B, Sparatore F.
Abstract : Quinolizidinyl derivatives of the tricyclic systems characterizing pirenzepine and nuvenzepine, were prepared and tested as ligands for muscarinic M1, M2 and M3 receptors; 5,11-dihydro-11-[(S-lupinyl)-thioacetyl]-6H-pyrido[2,3-b][1, 4]benzodiazepin-6-one exhibited IC50 = 10 nM for M1 and 760 nM for both M2 and M3 subtypes. During the synthesis some interesting side compounds were isolated and characterized.
|
Displacement of [3H]QNB (quinuclidinyl benzylate) from muscarinic M2 receptor of rat heart homogenates.
|
Rattus norvegicus
|
267.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design of dual acting anticonvulsant-antimuscarinic succinimide and hydantoin derivatives
Year : 1997
Volume : 7
Issue : 8
First Page : 979
Last Page : 984
Authors : Hudkins RL, DeHaven-Hudkins DL, Doukas P
|
Tested for affinity constant against M2 muscarinic receptor rat heart using [3H]-NMS
|
Rattus norvegicus
|
794.33
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological activity of methoctramine-related tetraamines bearing an 11-acetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one moiety: structural requirements for optimum occupancy of muscarinic receptor subtypes as revealed by symmetrical and unsymmetrical polyamines.
Year : 1994
Volume : 37
Issue : 20
First Page : 3363
Last Page : 3372
Authors : Minarini A, Bolognesi ML, Budriesi R, Canossa M, Chiarini A, Spampinato S, Melchiorre C.
Abstract : Tetraamines 5-13 and diamines 14-17 as well as monoamine 18 were synthesized, and their biological profiles at muscarinic receptor subtypes were assessed by functional experiments in isolated guinea pig left atrium (M2) and ileum (M3) and by binding assays in rat cortex (M1), heart (M2), and submaxillary gland (M3) homogenates and NG 108-15 cells (M4). An appropriate number and type of substituents on the terminal nitrogens of a tetraamine backbone afforded compounds, such as tripitramine (8) and dipitramine (6), which are endowed with different affinity and selectivity profiles. Tripitramine, a nonsymmetrical tetraamine, resulted in the most potent and the most selective M2 muscarinic receptor antagonist so far available (pA2 = 9.75 +/- 0.02; pKi = 9.54 +/- 0.08). However, it failed to discriminate between M1 and M4 muscarinic receptor subtypes (selectivity ratio: M2/M3, 1600-2200; M2/M1, 81; M2/M4, 41; M1/M3, 28; M4/M3, 55; M4/M1, 2). Dipitramine, another nonsymmetrical tetraamine bearing two substituents on the same terminal nitrogen, displayed the highest affinity for M1 muscarinic receptors (pKi = 8.60 +/- 0.15) and was able to differentiate, unlike 8, all four muscarinic receptor subtypes investigated (selectivity ratio: M1/M2, 5; M1/M3, 2700; M1/M4, 76; M2/M3, 260-520; M2/M4, 15; M4/M3, 35). The results are discussed in terms of a possible mode of interaction of tetraamines with muscarinic receptor subtypes.
|
Compound was tested for inhibiting [3H]N-Methyl-scopolamine Binding to Muscarinic receptor (M2) in Rat Heart
|
None
|
794.33
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological activity of some 4-DAMP- related compounds
Year : 1995
Volume : 5
Issue : 20
First Page : 2325
Last Page : 2330
Authors : Tumiatti V, Santi S, Recanatini M, Minarini A, Melchiorre C, Chiarini A, Budriesi R
|
Inhibition of binding of [3H]N-methylscopolamine to muscarinic receptor (M2) in rat heart homogenates
|
None
|
794.33
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological activity of some tetraamines related to methoctramine and 4-DAMP
Year : 1995
Volume : 5
Issue : 8
First Page : 785
Last Page : 790
Authors : Melchiorre C, Minarini A, Spampinato S, Tumiatti V
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of ventral dentate gyrus region of forebrain
|
Rattus norvegicus
|
210.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of ventral lateral geniculate region of midbrain
|
Rattus norvegicus
|
640.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of ventral parabrachial nucleus region of hindbrain
|
Rattus norvegicus
|
420.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of ventral posterior thalamic nucleus region of brain
|
Rattus norvegicus
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]l-quinuclidinyl benzilate ([3H]L-QNB) to muscarinic acetylcholine receptor of ventral subiculum region of forebrain
|
Rattus norvegicus
|
420.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Inhibition of binding of [3H]L-quinuclidinyl benzilate ([3H]-l-QNB) to muscarinic acetylcholine receptor of zona inserta region of midbrain
|
Rattus norvegicus
|
520.0
nM
|
|
Journal : J. Med. Chem.
Title : Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Year : 1989
Volume : 32
Issue : 6
First Page : 1164
Last Page : 1172
Authors : Messer WS, Ellerbrock BR, Smith DA, Hoss W.
Abstract : The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one [pirenzepine (compound I)] and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for M1 and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency than II for inhibition of [3H]-l-quinuclidinyl benzilate ([3H]-l-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence of multiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity for hippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 microM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 microM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greater than 1.0 microM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 microM) than to receptors in thalamic nuclei (IC50 values between 0.5 and 2.0 microM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 microM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinic receptor subtypes (as defined through cloning procedures) with selective ligands. Minimum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ring with respect to the tricyclic system. In contrast, the (diethylamino)methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that the greater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.
|
Binding affinity against Muscarinic acetylcholine receptor M1 by displacement of [3H]pirenzepine in bovine striatum
|
Bos taurus
|
3.6
nM
|
|
Journal : J. Med. Chem.
Title : Affinity and selectivity of the optical isomers of 3-quinuclidinyl benzilate and related muscarinic antagonists.
Year : 1988
Volume : 31
Issue : 7
First Page : 1463
Last Page : 1466
Authors : Rzeszotarski WJ, McPherson DW, Ferkany JW, Kinnier WJ, Noronha-Blob L, Kirkien-Rzeszotarski A.
Abstract : All of the optical isomers of the muscarinic antagonists 3-(1-azabicyclo[2.2.2]octyl) alpha-hydroxy-alpha,alpha-diphenylacetate (3-quinuclidinyl benzilate, QNB, 1) 3-(1-azabicyclo[2.2.2]octyl) xanthene-9-carboxylate (3-quinuclidinyl xanthene-9-carboxylate, QNX, 2), and 3-(1-azabicyclo[2.2.2]ocytl) alpha-hydroxy-alpha-phenylpropionate (3-quinuclidinyl atrolactate, QNA, 3) were prepared and studied in binding and functional assays. In all instances the esters of (R)-1-azabicyclo[2.2.2]octan-3-ol (3-quinuclidinol) had greater affinity for the M1 and M2 subpopulations of muscarinic acetylcholine receptors (M-AChRs) than did their S counterparts. The enantiomers of QNB (1), QNX (2), and QNA (3) in which the alcoholic portion of the muscarinic antagonists had the S absolute stereochemistry were more selective for the M1-AChRs. This selectivity was modulated by the nature and, in the case of QNA, the chirality of the acid portion. The most potent isomer in the series was (R)-QNB. In the QNA series the diastereoisomer with the absolute R configuration of the alcohol (a) and the R configuration of the acid (b) was the most potent in both binding and functional assays whereas (Sa,Rb)-QNA was the most selective for the M1 subtype of M-AChRs. In fact, the latter diastereomer was as potent and selective as pirenzepine for M1-AChRs.
|
Binding affinity against Muscarinic acetylcholine receptor M2 by displacement of [3H]QNB in rat myocardium
|
Rattus norvegicus
|
377.0
nM
|
|
Journal : J. Med. Chem.
Title : Affinity and selectivity of the optical isomers of 3-quinuclidinyl benzilate and related muscarinic antagonists.
Year : 1988
Volume : 31
Issue : 7
First Page : 1463
Last Page : 1466
Authors : Rzeszotarski WJ, McPherson DW, Ferkany JW, Kinnier WJ, Noronha-Blob L, Kirkien-Rzeszotarski A.
Abstract : All of the optical isomers of the muscarinic antagonists 3-(1-azabicyclo[2.2.2]octyl) alpha-hydroxy-alpha,alpha-diphenylacetate (3-quinuclidinyl benzilate, QNB, 1) 3-(1-azabicyclo[2.2.2]octyl) xanthene-9-carboxylate (3-quinuclidinyl xanthene-9-carboxylate, QNX, 2), and 3-(1-azabicyclo[2.2.2]ocytl) alpha-hydroxy-alpha-phenylpropionate (3-quinuclidinyl atrolactate, QNA, 3) were prepared and studied in binding and functional assays. In all instances the esters of (R)-1-azabicyclo[2.2.2]octan-3-ol (3-quinuclidinol) had greater affinity for the M1 and M2 subpopulations of muscarinic acetylcholine receptors (M-AChRs) than did their S counterparts. The enantiomers of QNB (1), QNX (2), and QNA (3) in which the alcoholic portion of the muscarinic antagonists had the S absolute stereochemistry were more selective for the M1-AChRs. This selectivity was modulated by the nature and, in the case of QNA, the chirality of the acid portion. The most potent isomer in the series was (R)-QNB. In the QNA series the diastereoisomer with the absolute R configuration of the alcohol (a) and the R configuration of the acid (b) was the most potent in both binding and functional assays whereas (Sa,Rb)-QNA was the most selective for the M1 subtype of M-AChRs. In fact, the latter diastereomer was as potent and selective as pirenzepine for M1-AChRs.
|
Displacement of [3H](-)-quinuclidinyl benzilate(QNB) from muscarinic (M2) receptor in rat heart homogenates
|
Rattus norvegicus
|
267.0
nM
|
|
Journal : J. Med. Chem.
Title : Muscarinic receptor binding profile of para-substituted caramiphen analogues.
Year : 1991
Volume : 34
Issue : 10
First Page : 2984
Last Page : 2989
Authors : Hudkins RL, DeHaven-Hudkins DL, Stubbins JF.
Abstract : Para-substituted analogues of the antimuscarinic agent caramiphen were synthesized and evaluated for their ability to bind to the M1 and M2 subtypes of the muscarinic receptor. The purpose of the set was to look for a possible relationship in binding affinity or receptor subtype selectivity with aromatic substituent parameters such as Hammett's sigma or Hansch's pi values. It is felt this could be determined initially with only four properly chosen substituents. In this approach, substituents were chosen which have an extreme value for sigma and for pi, in a positive and negative direction, in all combinations. The substituents chosen for examination were amino (-sigma, -pi); 1-pyrrolidinyl (-sigma, +pi); 1-tetrazolyl (+sigma, -pi), and iodo (+sigma, +pi). It was determined in this research that caramiphen binds with high affinity (Ki = 1.2 nM) and is selective for the M1 over M2 muscarinic receptor subtype (26-fold). An examination of para-substitution reveals that compounds with electron-withdrawing (+sigma) substituents showed M1 selectivity, while the derivatives with electron-donating groups (-sigma) were nonselective in the binding assays. On the basis of this finding, the nitro and cyano derivatives were prepared and found to be M1 selective. The + sigma derivatives showed a decrease in M2 affinity while the p-nitro and p-iodo derivatives retained approximately equal affinity as caramiphen for the M1 site. The nitro- and iodocaramiphen derivatives were as potent (M1, Ki = 5.52 and 2.11 nM, respectively) and showed a greater selectivity of M1 over M2 binding than the M1 prototypical agent pirenzepine (M1, Ki = 5.21 nM).
|
Inhibition of binding of [3H]N-methylscopolamine to muscarinic acetylcholine receptor M2 of rat heart tissue membrane.
|
None
|
610.0
nM
|
|
Journal : J. Med. Chem.
Title : Functionalized congener approach to muscarinic antagonists: analogues of pirenzepine.
Year : 1991
Volume : 34
Issue : 7
First Page : 2133
Last Page : 2145
Authors : Karton Y, Bradbury BJ, Baumgold J, Paek R, Jacobson KA.
Abstract : The M1-selective muscarinic receptor antagonist pirenzepine 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one) was derivatized to explore points of attachment of functionalized side chains for the synthesis of receptor probes and ligands for affinity chromatography. The analogues prepared were evaluated in competitive binding assays versus [3H]-N-methylscopolamine at four muscarinic receptor subtypes (m1AChR-m4AChR) in membranes from rat heart tissue and transfected A9L cells. 9-(Hydroxymethyl)pirenzepine, 8-(methylthio)pirenzepine, and a series of 8-aminosulfonyl derivatives were synthesized. Several 5-substituted analogues of pirenzepine also were prepared. An alternate series of analogues substituted on the 4-position of the piperazine ring was prepared by reaction of 4-desmethylpirenzepine with various electrophiles. An N-chloroethyl analogue of pirenzepine was shown to form a reactive aziridine species in aqueous buffer yet failed to affinity label muscarinic receptors. Within a series of aminoalkyl analogues, the affinity increased as the length of the alkyl chain increased. Shorter chain analogues were generally much less potent than pirenzepine, and longer analogues (7-10 carbons) were roughly as potent as pirenzepine at m1 receptors, but were nonselective. Depending on the methylene chain length, acylation or alkyl substitution of the terminal amine also influenced the affinity at muscarinic receptors.
|
Inhibition of stress-induced ulcer formation in rats by 10 mg/kg p.o. administration.
|
Rattus norvegicus
|
67.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiulcer activity of 5,11-dihydro[1]benzoxepino[3,4-b]pyridines.
Year : 1988
Volume : 31
Issue : 4
First Page : 779
Last Page : 785
Authors : Kumazawa T, Harakawa H, Obase H, Oiji Y, Tanaka H, Shuto K, Ishii A, Oka T, Nakamizo N.
Abstract : A series of substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines was synthesized and evaluated for antiulcer activity in water immersion/restrained stress ulcer assay in rats. Structure-activity relationships are described. Most of the tested compounds exhibited low affinity to the muscarinic acetylcholine receptor. The molecular features for the best activities are the 2-(diethylamino)ethylenediamine group at the 5-position of the oxepin ring and an oxepin skeleton rather than a thiepin or a pyran skeleton. Methyl and chlorine substitution on the benzene ring reduced the activity. Compound 11, 5-[[2-(diethylamino)ethyl]amino]-5,11-dihydro[1]benzoxepino [3,4-b]pyridine trihydrochloride was selected for further evaluation. Synthesis and antiulcer activity of optically active 11 is described. There were no statistically significant differences between (+)-, (-)-, and (+/-)-11. Compound 11 showed weak antisecretory activity in pylorus-ligated rats. It is now under clinical evaluation as KW 5805.
|
The antiulcer activity against stress-induced ulcer in rats by 30 mg/kg peroral administration.
|
Rattus norvegicus
|
86.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiulcer activity of 5,11-dihydro[1]benzoxepino[3,4-b]pyridines.
Year : 1988
Volume : 31
Issue : 4
First Page : 779
Last Page : 785
Authors : Kumazawa T, Harakawa H, Obase H, Oiji Y, Tanaka H, Shuto K, Ishii A, Oka T, Nakamizo N.
Abstract : A series of substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines was synthesized and evaluated for antiulcer activity in water immersion/restrained stress ulcer assay in rats. Structure-activity relationships are described. Most of the tested compounds exhibited low affinity to the muscarinic acetylcholine receptor. The molecular features for the best activities are the 2-(diethylamino)ethylenediamine group at the 5-position of the oxepin ring and an oxepin skeleton rather than a thiepin or a pyran skeleton. Methyl and chlorine substitution on the benzene ring reduced the activity. Compound 11, 5-[[2-(diethylamino)ethyl]amino]-5,11-dihydro[1]benzoxepino [3,4-b]pyridine trihydrochloride was selected for further evaluation. Synthesis and antiulcer activity of optically active 11 is described. There were no statistically significant differences between (+)-, (-)-, and (+/-)-11. Compound 11 showed weak antisecretory activity in pylorus-ligated rats. It is now under clinical evaluation as KW 5805.
|
Evaluated for the phosphatidyl inositol turnover at Muscarinic acetylcholine receptor M1 in rat cortex
|
Rattus norvegicus
|
8.1
nM
|
|
Journal : J. Med. Chem.
Title : Affinity and selectivity of the optical isomers of 3-quinuclidinyl benzilate and related muscarinic antagonists.
Year : 1988
Volume : 31
Issue : 7
First Page : 1463
Last Page : 1466
Authors : Rzeszotarski WJ, McPherson DW, Ferkany JW, Kinnier WJ, Noronha-Blob L, Kirkien-Rzeszotarski A.
Abstract : All of the optical isomers of the muscarinic antagonists 3-(1-azabicyclo[2.2.2]octyl) alpha-hydroxy-alpha,alpha-diphenylacetate (3-quinuclidinyl benzilate, QNB, 1) 3-(1-azabicyclo[2.2.2]octyl) xanthene-9-carboxylate (3-quinuclidinyl xanthene-9-carboxylate, QNX, 2), and 3-(1-azabicyclo[2.2.2]ocytl) alpha-hydroxy-alpha-phenylpropionate (3-quinuclidinyl atrolactate, QNA, 3) were prepared and studied in binding and functional assays. In all instances the esters of (R)-1-azabicyclo[2.2.2]octan-3-ol (3-quinuclidinol) had greater affinity for the M1 and M2 subpopulations of muscarinic acetylcholine receptors (M-AChRs) than did their S counterparts. The enantiomers of QNB (1), QNX (2), and QNA (3) in which the alcoholic portion of the muscarinic antagonists had the S absolute stereochemistry were more selective for the M1-AChRs. This selectivity was modulated by the nature and, in the case of QNA, the chirality of the acid portion. The most potent isomer in the series was (R)-QNB. In the QNA series the diastereoisomer with the absolute R configuration of the alcohol (a) and the R configuration of the acid (b) was the most potent in both binding and functional assays whereas (Sa,Rb)-QNA was the most selective for the M1 subtype of M-AChRs. In fact, the latter diastereomer was as potent and selective as pirenzepine for M1-AChRs.
|
Apparent dissociation constant for human muscarinic receptor M1 from FRET based binding assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Fluorescent pirenzepine derivatives as potential bitopic ligands of the human M1 muscarinic receptor.
Year : 2004
Volume : 47
Issue : 17
First Page : 4300
Last Page : 4315
Authors : Tahtaoui C, Parrot I, Klotz P, Guillier F, Galzi JL, Hibert M, Ilien B.
Abstract : Following a recent description of fluorescence resonance energy transfer between enhanced green fluorescent protein (EGFP)-fused human muscarinic M1 receptors and Bodipy-labeled pirenzepine, we synthesized seven fluorescent derivatives of this antagonist in order to further characterize ligand-receptor interactions. These compounds carry Bodipy [558/568], Rhodamine Red-X [560/580], or Fluorolink Cy3 [550/570] fluorophores connected to pirenzepine through various linkers. All molecules reversibly bind with high affinity to M1 receptors (radioligand and energy transfer binding experiments) provided that the linker contains more than six atoms. The energy transfer efficiency exhibits modest variations among ligands, indicating that the distance separating EGFP from the fluorophores remains almost constant. This also supports the notion that the fluorophores may bind to the receptor protein. Kinetic analyses reveal that the dissociation of two Bodipy derivatives (10 or 12 atom long linkers) is sensitive to the presence of the allosteric modulator brucine, while that of all other molecules (15-24 atom long linkers) is not. The data favor the idea that these analogues might interact with both the acetylcholine and the brucine binding domains.
|
Inhibition of [3H]QNB binding to human muscarinic receptor M1
|
Homo sapiens
|
23.5
nM
|
|
Journal : J. Med. Chem.
Title : Fluorescent pirenzepine derivatives as potential bitopic ligands of the human M1 muscarinic receptor.
Year : 2004
Volume : 47
Issue : 17
First Page : 4300
Last Page : 4315
Authors : Tahtaoui C, Parrot I, Klotz P, Guillier F, Galzi JL, Hibert M, Ilien B.
Abstract : Following a recent description of fluorescence resonance energy transfer between enhanced green fluorescent protein (EGFP)-fused human muscarinic M1 receptors and Bodipy-labeled pirenzepine, we synthesized seven fluorescent derivatives of this antagonist in order to further characterize ligand-receptor interactions. These compounds carry Bodipy [558/568], Rhodamine Red-X [560/580], or Fluorolink Cy3 [550/570] fluorophores connected to pirenzepine through various linkers. All molecules reversibly bind with high affinity to M1 receptors (radioligand and energy transfer binding experiments) provided that the linker contains more than six atoms. The energy transfer efficiency exhibits modest variations among ligands, indicating that the distance separating EGFP from the fluorophores remains almost constant. This also supports the notion that the fluorophores may bind to the receptor protein. Kinetic analyses reveal that the dissociation of two Bodipy derivatives (10 or 12 atom long linkers) is sensitive to the presence of the allosteric modulator brucine, while that of all other molecules (15-24 atom long linkers) is not. The data favor the idea that these analogues might interact with both the acetylcholine and the brucine binding domains.
|
Percent inhibition against Muscarinic acetylcholine receptor M1 at 1 uM
|
Homo sapiens
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine and analogues as A2A adenosine receptor antagonists. Design, synthesis, and pharmacological characterization.
Year : 2005
Volume : 48
Issue : 22
First Page : 6887
Last Page : 6896
Authors : Minetti P, Tinti MO, Carminati P, Castorina M, Di Cesare MA, Di Serio S, Gallo G, Ghirardi O, Giorgi F, Giorgi L, Piersanti G, Bartoccini F, Tarzia G.
Abstract : Two types of adenosine receptor ligands were designed, i.e., 9H-purine and 1H-imidazo[4,5-c]pyridines, to obtain selective A(2A) antagonists, and we report here their synthesis and binding affinities for the four adenosine receptor subtypes A(1), A(2A), A(2B) and A(3). The design was carried out on the basis of the molecular modeling of a number of potent adenosine receptor antagonists described in the literature. Three compounds (25b-d) showed an interesting affinity and selectivity for the A(2A) subtype. One of them, i.e., ST1535 (2-n-butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine, 25b) (K(i) A(2A) = 6.6 nM, K(i) A(1)/A(2A) = 12; K(i) A(2B)/A(2A) = 58; K(i) A(3)/A(2A) > 160), was selected for in vivo study and shown to induce a dose-related increase in locomotor activity, suggestive of an A(2A) antagonist type of activity.
|
Displacement of [3H]QNB from EGFP(delta-17)human M1 receptor expressed in HEK cells
|
Homo sapiens
|
23.5
nM
|
|
Journal : J. Med. Chem.
Title : On the use of nonfluorescent dye labeled ligands in FRET-based receptor binding studies.
Year : 2005
Volume : 48
Issue : 24
First Page : 7847
Last Page : 7859
Authors : Tahtaoui C, Guillier F, Klotz P, Galzi JL, Hibert M, Ilien B.
Abstract : The efficiency of fluorescence resonance energy transfer (FRET) is dependent upon donor-acceptor proximity and spectral overlap, whether the acceptor partner is fluorescent or not. We report here on the design, synthesis, and characterization of two novel pirenzepine derivatives that were coupled to patent blue VF and pinacyanol dyes. These nonfluorescent compounds, when added to cells stably expressing enhanced green fluorescent protein (EGFP)-fused muscarinic M1 receptors, promote EGFP fluorescence extinction in a time-, concentration-, and atropine-dependent manner. They display nanomolar affinity for the muscarinic receptor, determined using either FRET or classical radioligand binding conditions. We provide evidence that these compounds behave as potent acceptors of energy from excited EGFP with quenching efficiencies comparable to those of analogous fluorescent bodipy or rhodamine red pirenzepine derivatives. The advantages they offer over fluorescent ligands are illustrated and discussed in terms of reliability, sensitivity, and wider applicability of FRET-based receptor binding assays.
|
Displacement of [3H]QNB from human muscarinic M1 receptor expressed in CHO cells
|
Homo sapiens
|
21.38
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel oxotremorine-related heterocyclic derivatives: Synthesis and in vitro pharmacology at the muscarinic receptor subtypes.
Year : 2007
Volume : 15
Issue : 24
First Page : 7626
Last Page : 7637
Authors : Dallanoce C, De Amici M, Barocelli E, Bertoni S, Roth BL, Ernsberger P, De Micheli C.
Abstract : A set of novel heterocyclic ligands (6-27) structurally related to Oxotremorine 2 was designed, synthesized and tested at muscarinic receptor subtypes (mAChRs). In the binding experiments at cloned human receptors (hm1-5), compounds 7 and 15 evidenced a remarkable affinity and selectivity for the hm2 subtype. The in vitro functional assays, performed on a selected group of derivatives at M(1), M(2), and M(3) tissue preparations, singled out the 3-butynyloxy-5-methylisoxazole trimethylammonium salt 7 as a potent unselective muscarinic agonist [pEC(50): 7.40 (M(1)), 8.18 (M(2)), and 8.14 (M(3))], whereas its 5-phenyl analogue 12 behaved as a muscarinic antagonist, slightly selective for the M(1) subtype [pK(B): 6.88 (M(1)), 5.95 (M(2)), 5.53 (M(3))]. Moreover, the functional data put in evidence that the presence of the piperidine ring may generate a functional selectivity, e.g., an M(1) antagonist/M(2) partial agonist/M(3) full agonist profile (compound 21), at variance with the corresponding quaternary ammonium salt (compound 22) which behaved as a muscarinic agonist at all M(1-3) receptors, with an appreciable selectivity for the cardiac M(2) receptors.
|
Displacement of [3H]QNB from human muscarinic M5 receptor expressed in CHO cells
|
Homo sapiens
|
35.48
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel oxotremorine-related heterocyclic derivatives: Synthesis and in vitro pharmacology at the muscarinic receptor subtypes.
Year : 2007
Volume : 15
Issue : 24
First Page : 7626
Last Page : 7637
Authors : Dallanoce C, De Amici M, Barocelli E, Bertoni S, Roth BL, Ernsberger P, De Micheli C.
Abstract : A set of novel heterocyclic ligands (6-27) structurally related to Oxotremorine 2 was designed, synthesized and tested at muscarinic receptor subtypes (mAChRs). In the binding experiments at cloned human receptors (hm1-5), compounds 7 and 15 evidenced a remarkable affinity and selectivity for the hm2 subtype. The in vitro functional assays, performed on a selected group of derivatives at M(1), M(2), and M(3) tissue preparations, singled out the 3-butynyloxy-5-methylisoxazole trimethylammonium salt 7 as a potent unselective muscarinic agonist [pEC(50): 7.40 (M(1)), 8.18 (M(2)), and 8.14 (M(3))], whereas its 5-phenyl analogue 12 behaved as a muscarinic antagonist, slightly selective for the M(1) subtype [pK(B): 6.88 (M(1)), 5.95 (M(2)), 5.53 (M(3))]. Moreover, the functional data put in evidence that the presence of the piperidine ring may generate a functional selectivity, e.g., an M(1) antagonist/M(2) partial agonist/M(3) full agonist profile (compound 21), at variance with the corresponding quaternary ammonium salt (compound 22) which behaved as a muscarinic agonist at all M(1-3) receptors, with an appreciable selectivity for the cardiac M(2) receptors.
|
Inhibition of human muscarinic M1 receptor
|
Homo sapiens
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity.
Year : 2008
Volume : 51
Issue : 14
First Page : 4150
Last Page : 4169
Authors : Grice CA, Tays KL, Savall BM, Wei J, Butler CR, Axe FU, Bembenek SD, Fourie AM, Dunford PJ, Lundeen K, Coles F, Xue X, Riley JP, Williams KN, Karlsson L, Edwards JP.
Abstract : LTA 4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA 4H stereospecifically catalyzes the transformation of the unstable epoxide LTA 4 to the diol LTB 4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB 4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA 4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.
|
Displacement of [3H]N-methylscopolamine chloride from human cloned muscarinic M1 receptor expressed in CHOK1 cells
|
Homo sapiens
|
2.818
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of pirenzepine analogs bearing a 1,2-cyclohexanediamine and perhydroquinoxaline units in exchange for the piperazine ring as antimuscarinics.
Year : 2008
Volume : 16
Issue : 15
First Page : 7311
Last Page : 7320
Authors : Minarini A, Marucci G, Bellucci C, Giorgi G, Tumiatti V, Bolognesi ML, Matera R, Rosini M, Melchiorre C.
Abstract : Pirenzepine (2) is one of the most selective muscarinic M(1) versus M(2) receptor antagonists known. A series of 2 analogs, in which the piperazyl moiety was replaced by a cis- and trans-cyclohexane-1,2-diamine (3-6) or a trans- and cis-perhydroquinoxaline rings (7 and 8) were prepared, with the aim to investigate the role of the piperazine ring of 2 in the interaction with the muscarinic receptors. The structural change leading to compounds 3-6 abolished in binding assays the muscarinic M(1)/M(2) selectivity of 2, due to an increased M(2) affinity. Rather, compounds 3-6 displayed a reversed selectivity showing more affinity at the muscarinic M(2) receptor than at all the other subtypes tested.
|
Displacement of [3H]N-methylscopolamine chloride from human cloned muscarinic M2 receptor expressed in CHOK1 cells
|
Homo sapiens
|
173.78
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of pirenzepine analogs bearing a 1,2-cyclohexanediamine and perhydroquinoxaline units in exchange for the piperazine ring as antimuscarinics.
Year : 2008
Volume : 16
Issue : 15
First Page : 7311
Last Page : 7320
Authors : Minarini A, Marucci G, Bellucci C, Giorgi G, Tumiatti V, Bolognesi ML, Matera R, Rosini M, Melchiorre C.
Abstract : Pirenzepine (2) is one of the most selective muscarinic M(1) versus M(2) receptor antagonists known. A series of 2 analogs, in which the piperazyl moiety was replaced by a cis- and trans-cyclohexane-1,2-diamine (3-6) or a trans- and cis-perhydroquinoxaline rings (7 and 8) were prepared, with the aim to investigate the role of the piperazine ring of 2 in the interaction with the muscarinic receptors. The structural change leading to compounds 3-6 abolished in binding assays the muscarinic M(1)/M(2) selectivity of 2, due to an increased M(2) affinity. Rather, compounds 3-6 displayed a reversed selectivity showing more affinity at the muscarinic M(2) receptor than at all the other subtypes tested.
|
Displacement of [3H]N-methylscopolamine chloride from human cloned muscarinic M3 receptor expressed in CHOK1 cells
|
Homo sapiens
|
47.86
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of pirenzepine analogs bearing a 1,2-cyclohexanediamine and perhydroquinoxaline units in exchange for the piperazine ring as antimuscarinics.
Year : 2008
Volume : 16
Issue : 15
First Page : 7311
Last Page : 7320
Authors : Minarini A, Marucci G, Bellucci C, Giorgi G, Tumiatti V, Bolognesi ML, Matera R, Rosini M, Melchiorre C.
Abstract : Pirenzepine (2) is one of the most selective muscarinic M(1) versus M(2) receptor antagonists known. A series of 2 analogs, in which the piperazyl moiety was replaced by a cis- and trans-cyclohexane-1,2-diamine (3-6) or a trans- and cis-perhydroquinoxaline rings (7 and 8) were prepared, with the aim to investigate the role of the piperazine ring of 2 in the interaction with the muscarinic receptors. The structural change leading to compounds 3-6 abolished in binding assays the muscarinic M(1)/M(2) selectivity of 2, due to an increased M(2) affinity. Rather, compounds 3-6 displayed a reversed selectivity showing more affinity at the muscarinic M(2) receptor than at all the other subtypes tested.
|
Displacement of [3H]N-methylscopolamine chloride from human cloned muscarinic M4 receptor expressed in CHOK1 cells
|
Homo sapiens
|
13.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of pirenzepine analogs bearing a 1,2-cyclohexanediamine and perhydroquinoxaline units in exchange for the piperazine ring as antimuscarinics.
Year : 2008
Volume : 16
Issue : 15
First Page : 7311
Last Page : 7320
Authors : Minarini A, Marucci G, Bellucci C, Giorgi G, Tumiatti V, Bolognesi ML, Matera R, Rosini M, Melchiorre C.
Abstract : Pirenzepine (2) is one of the most selective muscarinic M(1) versus M(2) receptor antagonists known. A series of 2 analogs, in which the piperazyl moiety was replaced by a cis- and trans-cyclohexane-1,2-diamine (3-6) or a trans- and cis-perhydroquinoxaline rings (7 and 8) were prepared, with the aim to investigate the role of the piperazine ring of 2 in the interaction with the muscarinic receptors. The structural change leading to compounds 3-6 abolished in binding assays the muscarinic M(1)/M(2) selectivity of 2, due to an increased M(2) affinity. Rather, compounds 3-6 displayed a reversed selectivity showing more affinity at the muscarinic M(2) receptor than at all the other subtypes tested.
|
Antagonist activity at peripheral muscarinic M2 receptor in guinea pig left atrium assessed as effect on arecaidin propargyl ester-induced contraction after 1 hr
|
Cavia porcellus
|
338.84
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of pirenzepine analogs bearing a 1,2-cyclohexanediamine and perhydroquinoxaline units in exchange for the piperazine ring as antimuscarinics.
Year : 2008
Volume : 16
Issue : 15
First Page : 7311
Last Page : 7320
Authors : Minarini A, Marucci G, Bellucci C, Giorgi G, Tumiatti V, Bolognesi ML, Matera R, Rosini M, Melchiorre C.
Abstract : Pirenzepine (2) is one of the most selective muscarinic M(1) versus M(2) receptor antagonists known. A series of 2 analogs, in which the piperazyl moiety was replaced by a cis- and trans-cyclohexane-1,2-diamine (3-6) or a trans- and cis-perhydroquinoxaline rings (7 and 8) were prepared, with the aim to investigate the role of the piperazine ring of 2 in the interaction with the muscarinic receptors. The structural change leading to compounds 3-6 abolished in binding assays the muscarinic M(1)/M(2) selectivity of 2, due to an increased M(2) affinity. Rather, compounds 3-6 displayed a reversed selectivity showing more affinity at the muscarinic M(2) receptor than at all the other subtypes tested.
|
Antagonist activity at peripheral muscarinic M3 receptor in guinea pig longitudinal ileum assessed as effect on arecaidin propargyl ester-induced contraction after 1 hr
|
Cavia porcellus
|
131.83
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of pirenzepine analogs bearing a 1,2-cyclohexanediamine and perhydroquinoxaline units in exchange for the piperazine ring as antimuscarinics.
Year : 2008
Volume : 16
Issue : 15
First Page : 7311
Last Page : 7320
Authors : Minarini A, Marucci G, Bellucci C, Giorgi G, Tumiatti V, Bolognesi ML, Matera R, Rosini M, Melchiorre C.
Abstract : Pirenzepine (2) is one of the most selective muscarinic M(1) versus M(2) receptor antagonists known. A series of 2 analogs, in which the piperazyl moiety was replaced by a cis- and trans-cyclohexane-1,2-diamine (3-6) or a trans- and cis-perhydroquinoxaline rings (7 and 8) were prepared, with the aim to investigate the role of the piperazine ring of 2 in the interaction with the muscarinic receptors. The structural change leading to compounds 3-6 abolished in binding assays the muscarinic M(1)/M(2) selectivity of 2, due to an increased M(2) affinity. Rather, compounds 3-6 displayed a reversed selectivity showing more affinity at the muscarinic M(2) receptor than at all the other subtypes tested.
|
Antagonist activity at peripheral muscarinic M4 receptor in rabbit vas deferens assessed as effect on McN-A-343-induced contraction after 1 hr
|
Oryctolagus cuniculus
|
8.913
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of pirenzepine analogs bearing a 1,2-cyclohexanediamine and perhydroquinoxaline units in exchange for the piperazine ring as antimuscarinics.
Year : 2008
Volume : 16
Issue : 15
First Page : 7311
Last Page : 7320
Authors : Minarini A, Marucci G, Bellucci C, Giorgi G, Tumiatti V, Bolognesi ML, Matera R, Rosini M, Melchiorre C.
Abstract : Pirenzepine (2) is one of the most selective muscarinic M(1) versus M(2) receptor antagonists known. A series of 2 analogs, in which the piperazyl moiety was replaced by a cis- and trans-cyclohexane-1,2-diamine (3-6) or a trans- and cis-perhydroquinoxaline rings (7 and 8) were prepared, with the aim to investigate the role of the piperazine ring of 2 in the interaction with the muscarinic receptors. The structural change leading to compounds 3-6 abolished in binding assays the muscarinic M(1)/M(2) selectivity of 2, due to an increased M(2) affinity. Rather, compounds 3-6 displayed a reversed selectivity showing more affinity at the muscarinic M(2) receptor than at all the other subtypes tested.
|
Displacement of radiolabeled pirenzepine from human muscarinic M1 receptor
|
Homo sapiens
|
29.0
nM
|
|
Displacement of radiolabeled pirenzepine from human muscarinic M1 receptor
|
Homo sapiens
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia.
Year : 2008
Volume : 51
Issue : 22
First Page : 7094
Last Page : 7098
Authors : Liu H, Altenbach RJ, Carr TL, Chandran P, Hsieh GC, Lewis LG, Manelli AM, Milicic I, Marsh KC, Miller TR, Strakhova MI, Vortherms TA, Wakefield BD, Wetter JM, Witte DG, Honore P, Esbenshade TA, Brioni JD, Cowart MD.
Abstract : cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.
|
Inhibition of human muscarinic M1 receptor
|
Homo sapiens
|
19.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: design, synthesis, and structure-activity relationships.
Year : 2010
Volume : 18
Issue : 21
First Page : 7675
Last Page : 7699
Authors : Hayashi S, Nakata E, Morita A, Mizuno K, Yamamura K, Kato A, Ohashi K.
Abstract : Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C- and Aδ-fibers. In this study, design, synthesis, and structure-activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects.
|
Displacement of [3H]QNB from Drosophila melanogaster mAChR by scintillation counting
|
Drosophila melanogaster
|
430.0
nM
|
|
Journal : J Agric Food Chem
Title : Insect muscarinic acetylcholine receptor: pharmacological and toxicological profiles of antagonists and agonists.
Year : 2007
Volume : 55
Issue : 6
First Page : 2276
Last Page : 2281
Authors : Honda H, Tomizawa M, Casida JE.
Abstract : The insect muscarinic acetylcholine receptor (mAChR) is evaluated as a potential target for insecticide action. The mammalian M2/M4-selective antagonist radioligand [3H]AF-DX 384 (a pirenzepine analogue) binds to Drosophila mAChR at a single high-affinity site identical to that for the nonselective antagonist [3H]quinuclidinyl benzilate (QNB) and with a pharmacological profile distinct from that of all mammalian mAChR subtypes. Three nonselective antagonists (QNB, scopolamine, and atropine) show the highest affinity (Ki=0.5-2.4 nM) at the Drosophila target, and AF-DX 384 and M3-selective 4-DAMP (dimethyl-4-(diphenylacetoxy)piperidinium iodide) rank next in potency (Ki=5-18 nM). Eleven muscarinic antagonists generally exhibit higher affinity than eight agonists. On injection into houseflies, the antagonists 4-DAMP and (S)-(+)-dimethindene produce suppressed movement, the agonist (methyloxadiazolyl)quinuclidine causes knockdown and tremors, and all of them inhibit [3H]QNB binding ex vivo, indicating possible mAChR-mediated intoxication. The insect mAChR warrants continuing study in lead generation to discover novel insecticides.
|
Displacement of [3H]AF-DX 384 from Drosophila melanogaster mAChR by scintillation counting
|
Drosophila melanogaster
|
390.0
nM
|
|
Journal : J Agric Food Chem
Title : Insect muscarinic acetylcholine receptor: pharmacological and toxicological profiles of antagonists and agonists.
Year : 2007
Volume : 55
Issue : 6
First Page : 2276
Last Page : 2281
Authors : Honda H, Tomizawa M, Casida JE.
Abstract : The insect muscarinic acetylcholine receptor (mAChR) is evaluated as a potential target for insecticide action. The mammalian M2/M4-selective antagonist radioligand [3H]AF-DX 384 (a pirenzepine analogue) binds to Drosophila mAChR at a single high-affinity site identical to that for the nonselective antagonist [3H]quinuclidinyl benzilate (QNB) and with a pharmacological profile distinct from that of all mammalian mAChR subtypes. Three nonselective antagonists (QNB, scopolamine, and atropine) show the highest affinity (Ki=0.5-2.4 nM) at the Drosophila target, and AF-DX 384 and M3-selective 4-DAMP (dimethyl-4-(diphenylacetoxy)piperidinium iodide) rank next in potency (Ki=5-18 nM). Eleven muscarinic antagonists generally exhibit higher affinity than eight agonists. On injection into houseflies, the antagonists 4-DAMP and (S)-(+)-dimethindene produce suppressed movement, the agonist (methyloxadiazolyl)quinuclidine causes knockdown and tremors, and all of them inhibit [3H]QNB binding ex vivo, indicating possible mAChR-mediated intoxication. The insect mAChR warrants continuing study in lead generation to discover novel insecticides.
|
Binding affinity to human M5 muscarinic receptor
|
Homo sapiens
|
126.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural modifications to tetrahydropyridine-3-carboxylate esters en route to the discovery of M5-preferring muscarinic receptor orthosteric antagonists.
Year : 2013
Volume : 56
Issue : 4
First Page : 1693
Last Page : 1703
Authors : Zheng G, Smith AM, Huang X, Subramanian KL, Siripurapu KB, Deaciuc A, Zhan CG, Dwoskin LP.
Abstract : The M5 muscarinic acetylcholine receptor is suggested to be a potential pharmacotherapeutic target for the treatment of drug abuse. We describe herein the discovery of a series of M5-preferring orthosteric antagonists based on the scaffold of 1,2,5,6-tetrahydropyridine-3-carboxylic acid. Compound 56, the most selective compound in this series, possesses an 11-fold selectivity for the M5 over M1 receptor and shows little activity at M2-M4. This compound, although exhibiting modest affinity (K(i) = 2.24 μM) for the [(3)H]N-methylscopolamine binding site on the M5 receptor, is potent (IC50 = 0.45 nM) in inhibiting oxotremorine-evoked [(3)H]DA release from rat striatal slices. Further, a homology model of human M5 receptor based on the crystal structure of the rat M3 receptor was constructed, and docking studies of compounds 28 and 56 were performed in an attempt to understand the possible binding mode of these novel analogues to the receptor.
|
Binding affinity to human M4 muscarinic receptor
|
Homo sapiens
|
105.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural modifications to tetrahydropyridine-3-carboxylate esters en route to the discovery of M5-preferring muscarinic receptor orthosteric antagonists.
Year : 2013
Volume : 56
Issue : 4
First Page : 1693
Last Page : 1703
Authors : Zheng G, Smith AM, Huang X, Subramanian KL, Siripurapu KB, Deaciuc A, Zhan CG, Dwoskin LP.
Abstract : The M5 muscarinic acetylcholine receptor is suggested to be a potential pharmacotherapeutic target for the treatment of drug abuse. We describe herein the discovery of a series of M5-preferring orthosteric antagonists based on the scaffold of 1,2,5,6-tetrahydropyridine-3-carboxylic acid. Compound 56, the most selective compound in this series, possesses an 11-fold selectivity for the M5 over M1 receptor and shows little activity at M2-M4. This compound, although exhibiting modest affinity (K(i) = 2.24 μM) for the [(3)H]N-methylscopolamine binding site on the M5 receptor, is potent (IC50 = 0.45 nM) in inhibiting oxotremorine-evoked [(3)H]DA release from rat striatal slices. Further, a homology model of human M5 receptor based on the crystal structure of the rat M3 receptor was constructed, and docking studies of compounds 28 and 56 were performed in an attempt to understand the possible binding mode of these novel analogues to the receptor.
|
Binding affinity to human M2 muscarinic receptor
|
Homo sapiens
|
524.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural modifications to tetrahydropyridine-3-carboxylate esters en route to the discovery of M5-preferring muscarinic receptor orthosteric antagonists.
Year : 2013
Volume : 56
Issue : 4
First Page : 1693
Last Page : 1703
Authors : Zheng G, Smith AM, Huang X, Subramanian KL, Siripurapu KB, Deaciuc A, Zhan CG, Dwoskin LP.
Abstract : The M5 muscarinic acetylcholine receptor is suggested to be a potential pharmacotherapeutic target for the treatment of drug abuse. We describe herein the discovery of a series of M5-preferring orthosteric antagonists based on the scaffold of 1,2,5,6-tetrahydropyridine-3-carboxylic acid. Compound 56, the most selective compound in this series, possesses an 11-fold selectivity for the M5 over M1 receptor and shows little activity at M2-M4. This compound, although exhibiting modest affinity (K(i) = 2.24 μM) for the [(3)H]N-methylscopolamine binding site on the M5 receptor, is potent (IC50 = 0.45 nM) in inhibiting oxotremorine-evoked [(3)H]DA release from rat striatal slices. Further, a homology model of human M5 receptor based on the crystal structure of the rat M3 receptor was constructed, and docking studies of compounds 28 and 56 were performed in an attempt to understand the possible binding mode of these novel analogues to the receptor.
|
Binding affinity to human M3 muscarinic receptor
|
Homo sapiens
|
158.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural modifications to tetrahydropyridine-3-carboxylate esters en route to the discovery of M5-preferring muscarinic receptor orthosteric antagonists.
Year : 2013
Volume : 56
Issue : 4
First Page : 1693
Last Page : 1703
Authors : Zheng G, Smith AM, Huang X, Subramanian KL, Siripurapu KB, Deaciuc A, Zhan CG, Dwoskin LP.
Abstract : The M5 muscarinic acetylcholine receptor is suggested to be a potential pharmacotherapeutic target for the treatment of drug abuse. We describe herein the discovery of a series of M5-preferring orthosteric antagonists based on the scaffold of 1,2,5,6-tetrahydropyridine-3-carboxylic acid. Compound 56, the most selective compound in this series, possesses an 11-fold selectivity for the M5 over M1 receptor and shows little activity at M2-M4. This compound, although exhibiting modest affinity (K(i) = 2.24 μM) for the [(3)H]N-methylscopolamine binding site on the M5 receptor, is potent (IC50 = 0.45 nM) in inhibiting oxotremorine-evoked [(3)H]DA release from rat striatal slices. Further, a homology model of human M5 receptor based on the crystal structure of the rat M3 receptor was constructed, and docking studies of compounds 28 and 56 were performed in an attempt to understand the possible binding mode of these novel analogues to the receptor.
|
Binding affinity to human M1 muscarinic receptor
|
Homo sapiens
|
9.1
nM
|
|
Journal : J. Med. Chem.
Title : Structural modifications to tetrahydropyridine-3-carboxylate esters en route to the discovery of M5-preferring muscarinic receptor orthosteric antagonists.
Year : 2013
Volume : 56
Issue : 4
First Page : 1693
Last Page : 1703
Authors : Zheng G, Smith AM, Huang X, Subramanian KL, Siripurapu KB, Deaciuc A, Zhan CG, Dwoskin LP.
Abstract : The M5 muscarinic acetylcholine receptor is suggested to be a potential pharmacotherapeutic target for the treatment of drug abuse. We describe herein the discovery of a series of M5-preferring orthosteric antagonists based on the scaffold of 1,2,5,6-tetrahydropyridine-3-carboxylic acid. Compound 56, the most selective compound in this series, possesses an 11-fold selectivity for the M5 over M1 receptor and shows little activity at M2-M4. This compound, although exhibiting modest affinity (K(i) = 2.24 μM) for the [(3)H]N-methylscopolamine binding site on the M5 receptor, is potent (IC50 = 0.45 nM) in inhibiting oxotremorine-evoked [(3)H]DA release from rat striatal slices. Further, a homology model of human M5 receptor based on the crystal structure of the rat M3 receptor was constructed, and docking studies of compounds 28 and 56 were performed in an attempt to understand the possible binding mode of these novel analogues to the receptor.
|
Inhibition of muscarinic acetylcholine receptor in rat cortex
|
Rattus norvegicus
|
28.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of subtype selective muscarinic receptor antagonists as alternatives to atropine using in silico pharmacophore modeling and virtual screening methods.
Year : 2013
Volume : 21
Issue : 9
First Page : 2651
Last Page : 2662
Authors : Bhattacharjee AK, Pomponio JW, Evans SA, Pervitsky D, Gordon RK.
Abstract : Muscarinic acetylcholine receptors (mAChRs) have five known subtypes which are widely distributed in both the peripheral and central nervous system for regulation of a variety of cholinergic functions. Atropine is a well known muscarinic subtype non-specific antagonist that competitively inhibits acetylcholine (ACh) at postganglionic muscarinic sites. Atropine is used to treat organophosphate (OP) poisoning and resulting seizures in the warfighter because it competitively inhibits acetylcholine (ACh) at the muscarinic cholinergic receptors. ACh accumulates due to OP inhibition of acetylcholinesterase (AChE), the enzyme that hydrolyzes ACh. However, atropine produces several unwanted side-effects including dilated pupils, blurred vision, light sensitivity, and dry mouth. To overcome these side-effects, our goal was to find an alternative to atropine that emphasizes M1 (seizure prevention) antagonism but has minimum M2 (cardiac) and M3 (e.g., eye) antagonism so that an effective less toxic medical countermeasure may be developed to protect the warfighter against OP and other chemical warfare agents (CWAs). We adopted an in silico pharmacophore modeling strategy to develop features that are characteristics of known M1 subtype-selective compounds and used the model to identify several antagonists by screening an in-house (WRAIR-CIS) compound database. The generated model for the M1 selectivity was found to contain two hydrogen bond acceptors, one aliphatic hydrophobic, and one ring aromatic feature distributed in a 3D space. From an initial identification of about five hundred compounds, 173 compounds were selected through principal component and cluster analyses and in silico ADME/Toxicity evaluations. Next, these selected compounds were evaluated in a subtype-selective in vitro radioligand binding assay. Twenty eight of the compounds showed antimuscarinic activity. Nine compounds showed specificity for M1 receptors and low specificity for M3 receptors. The pK(i) values of the compounds range from 4.5 to 8.5 nM in comparison to a value of 8.7 nM for atropine. 2-(diethylamino)ethyl 2,2-diphenylpropanoate (ZW62841) was found have the best desired selectivity. None of the newly found compounds were previously reported to exhibit antimuscarinic specificity. Both theoretical and experimental results are presented.
|
Binding affinity to human muscarinic M1 receptor by radioligand displacement assay
|
Homo sapiens
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide stereoisomers as novel positive allosteric modulators of sigma-1 receptor.
Year : 2013
Volume : 21
Issue : 10
First Page : 2764
Last Page : 2771
Authors : Veinberg G, Vorona M, Zvejniece L, Vilskersts R, Vavers E, Liepinsh E, Kazoka H, Belyakov S, Mishnev A, Kuznecovs J, Vikainis S, Orlova N, Lebedev A, Ponomaryov Y, Dambrova M.
Abstract : Novel positive allosteric modulators of sigma-1 receptor represented by 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide enantiomers were synthesised using an asymmetric Michael addition of 2-nitroprop-1-enylbenzene to diethyl malonate. Following the chromatographic separation of the methyl erythro- and threo-4-nitro-3R- and 3S-phenylpentanoate diastereoisomers, target compounds were obtained by their reductive cyclisation into 5-methyl-4-phenylpyrrolidin-2-one enantiomers and the attachment of the acetamide group to the heterocyclic nitrogen. Experiments with electrically stimulated rat vas deference contractions induced by the PRE-084, an agonist of sigma-1 receptor, showed that (4R,5S)- and (4R,5R)-2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamides with an R-configuration at the C-4 chiral centre in the 2-pyrrolidone ring were more effective positive allosteric modulators of sigma-1 receptor than were their optical antipodes.
|
Binding affinity to human muscarinic M1 receptor by radioligand displacement assay
|
Homo sapiens
|
10.0
nM
|
|
Binding affinity to human muscarinic M1 receptor by radioligand displacement assay
|
Homo sapiens
|
12.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and structure-activity relationship studies in serotonin 5-HT(1A) receptor agonists based on fused pyrrolidone scaffolds.
Year : 2013
Volume : 63
First Page : 85
Last Page : 94
Authors : Cappelli A, Manini M, Valenti S, Castriconi F, Giuliani G, Anzini M, Brogi S, Butini S, Gemma S, Campiani G, Giorgi G, Mennuni L, Lanza M, Giordani A, Caselli G, Letari O, Makovec F.
Abstract : A new class of serotonin 5-HT1A receptor ligands related to NAN-190, buspirone and aripiprazole has been designed using our potent 5-HT3 receptor ligands as templates. The designed pyrrolidone derivatives 10a-n were prepared by means of the straightforward chemistry consisting in the reaction of the appropriate γ-haloester derivatives with the suitable arylpiperazinylalkylamines. The nanomolar 5-HT1A receptor affinity and the agonist-like profile shown by fused pyrrolidone derivatives 10k,m stimulated the rationalization of the interaction with an homology model of the 5-HT1A receptor and the evaluation of their selectivity profiles and the pharmacokinetic properties. Interestingly, the results of the profiling assays suggested for close congeners 10k,m a significantly divergent binding pattern with compound 10m showing an appreciable selectivity for 5-HT1AR.
|
Displacement of [3H]pirenzepine from human recombinant M1 receptor expressed in CHO cells
|
Homo sapiens
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel arylsulfonamide derivatives with 5-HT₆/5-HT₇ receptor antagonism targeting behavioral and psychological symptoms of dementia.
Year : 2014
Volume : 57
Issue : 11
First Page : 4543
Last Page : 4557
Authors : Kołaczkowski M, Marcinkowska M, Bucki A, Pawłowski M, Mitka K, Jaśkowska J, Kowalski P, Kazek G, Siwek A, Wasik A, Wesołowska A, Mierzejewski P, Bienkowski P.
Abstract : In order to target behavioral and psychological symptoms of dementia (BPSD), we used molecular modeling-assisted design to obtain novel multifunctional arylsulfonamide derivatives that potently antagonize 5-HT(6/7/2A) and D2 receptors, without interacting with M1 receptors and hERG channels. In vitro studies confirmed their antagonism of 5-HT(7/2A) and D2 receptors and weak interactions with key antitargets (M1R and hERG) associated with side effects. Marked 5-HT6 receptor affinities were also observed, notably for 6-fluoro-3-(piperidin-4-yl)-1,2-benzoxazole derivatives connected by a 3-4 unit alkyl linker with mono- or bicyclic, lipophilic arylsulfonamide moieties. N-[4-[4-(6-Fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]butyl]benzothiophene-2-sulfonamide (72) was characterized in vitro on 14 targets and antitargets. It displayed dual blockade of 5-HT6 and D2 receptors and negligible interactions at hERG and M1 receptors. Unlike reference antipsychotics, 72 displayed marked antipsychotic and antidepressant activity in rats after oral administration, in the absence of cognitive or motor impairment. This profile is particularly attractive when targeting a fragile, elderly BPSD patient population.
|
Antagonist activity at human M1 receptor expressed in HEK293T cells assessed as inhibition of carbachol-induced response by BRET based Gq protein engagement assay
|
Homo sapiens
|
48.98
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1).
Year : 2014
Volume : 57
Issue : 21
First Page : 9065
Last Page : 9077
Authors : Bonifazi A, Yano H, Del Bello F, Farande A, Quaglia W, Petrelli R, Matucci R, Nesi M, Vistoli G, Ferré S, Piergentili A.
Abstract : Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.
|
Antagonist activity at human M1 receptor expressed in HEK293T cells assessed as inhibition of carbachol-induced response by BRET based Gq protein activation assay
|
Homo sapiens
|
20.42
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1).
Year : 2014
Volume : 57
Issue : 21
First Page : 9065
Last Page : 9077
Authors : Bonifazi A, Yano H, Del Bello F, Farande A, Quaglia W, Petrelli R, Matucci R, Nesi M, Vistoli G, Ferré S, Piergentili A.
Abstract : Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.
|
Antagonist activity at human M1 receptor expressed in HEK293T cells assessed as inhibition of carbachol-induced response by BRET based beta-arrestin engagement assay
|
Homo sapiens
|
1.479
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1).
Year : 2014
Volume : 57
Issue : 21
First Page : 9065
Last Page : 9077
Authors : Bonifazi A, Yano H, Del Bello F, Farande A, Quaglia W, Petrelli R, Matucci R, Nesi M, Vistoli G, Ferré S, Piergentili A.
Abstract : Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.
|
Antagonist activity at human M4 receptor expressed in HEK293T cells assessed as inhibition of carbachol-induced response by beta-arrestin engagement assay
|
Homo sapiens
|
1.148
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1).
Year : 2014
Volume : 57
Issue : 21
First Page : 9065
Last Page : 9077
Authors : Bonifazi A, Yano H, Del Bello F, Farande A, Quaglia W, Petrelli R, Matucci R, Nesi M, Vistoli G, Ferré S, Piergentili A.
Abstract : Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.
|
Antagonist activity at human m1 muscarinic acetylcholine receptor expressed in HEK293 cells assessed as inhibition of acetylcholine-induced calcium mobilization at 10 microM by FLIPR assay
|
Homo sapiens
|
96.7
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of isoxazoline derivatives as potent M₁ muscarinic acetylcholine receptor agonists.
Year : 2015
Volume : 25
Issue : 7
First Page : 1546
Last Page : 1551
Authors : Huang M, Suk DH, Cho NC, Bhattarai D, Kang SB, Kim Y, Pae AN, Rhim H, Keum G.
Abstract : A series of azacyclic compounds substituted with isoxazole and 5-substituted isoxazolines were synthesized as acyclic modifications of the oxime class M1 mACh receptor agonist. Among them, 3-(tetrahydropyrin-3-yl)-5-(2-pyrrolodin-1-yl)isoxazoline compound 4f displayed potent and selective M1 mACh receptor agonist activity in the functional calcium mobilization assay (EC50=31 nM). Introduction of 2-pyrrolidinone and 3-tetrahydropyridine groups are pivotal to the high potency. Moreover, 4f was found to facilitate non-amyloidogenic amyloid precursor protein (APP) processing by significantly increasing ERK1/2 phosphorylation and sAPPα secretion, known disease-modifying effects related to M1 mAChR agonists in Alzheimer's disease (AD).
|
Inhibition of muscarinic M1 receptor (unknown origin) assessed as reduction in control ligand binding
|
Homo sapiens
|
15.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel 5-HT6 receptor antagonists/D2 receptor partial agonists targeting behavioral and psychological symptoms of dementia.
Year : 2015
Volume : 92
First Page : 221
Last Page : 235
Authors : Kołaczkowski M, Marcinkowska M, Bucki A, Śniecikowska J, Pawłowski M, Kazek G, Siwek A, Jastrzębska-Więsek M, Partyka A, Wasik A, Wesołowska A, Mierzejewski P, Bienkowski P.
Abstract : We describe a novel class of designed multiple ligands (DMLs) combining serotonin 5-HT6 receptor (5-HT6R) antagonism with dopamine D2 receptor (D2R) partial agonism. Prototype hybrid molecules were designed using docking to receptor homology models. Diverse pharmacophore moieties yielded 3 series of hybrids with varying in vitro properties at 5-HT6R and D2R, and at M1 receptor and hERG channel antitargets. 4-(piperazin-1-yl)-1H-indole derivatives showed highest antagonist potency at 5-HT6R, with 7-butoxy-3,4-dihydroquinolin-2(1H)-one and 2-propoxybenzamide derivatives having promising D2R partial agonism. 2-(3-(4-(1-(phenylsulfonyl)-1H-indol-4-yl)piperazin-1-yl)propoxy)benzamide (47) exhibited nanomolar affinity at both 5-HT6R and D2R and was evaluated in rat models. It displayed potent antidepressant-like and anxiolytic-like activity in the Porsolt and Vogel tests, respectively, more pronounced than that of a reference selective 5-HT6R antagonist or D2R partial agonist. In addition, 47 also showed antidepressant-like activity (Porsolt's test) and anxiolytic-like activity (open field test) in aged (>18-month old) rats. In operant conditioning tests, 47 enhanced responding for sweet reward in the saccharin self-administration test, consistent with anti-anhedonic properties. Further, 47 facilitated extinction of non-reinforced responding for sweet reward, suggesting potential procognitive activity. Taken together, these studies suggest that DMLs combining 5-HT6R antagonism and D2R partial agonism may successfully target affective disorders in patients from different age groups without a risk of cognitive deficits.
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Displacement of [3H]pirenzepine from human muscarinic M1 receptor expressed in CHO cells
|
Homo sapiens
|
16.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel 5-HT6 receptor antagonists/D2 receptor partial agonists targeting behavioral and psychological symptoms of dementia.
Year : 2015
Volume : 92
First Page : 221
Last Page : 235
Authors : Kołaczkowski M, Marcinkowska M, Bucki A, Śniecikowska J, Pawłowski M, Kazek G, Siwek A, Jastrzębska-Więsek M, Partyka A, Wasik A, Wesołowska A, Mierzejewski P, Bienkowski P.
Abstract : We describe a novel class of designed multiple ligands (DMLs) combining serotonin 5-HT6 receptor (5-HT6R) antagonism with dopamine D2 receptor (D2R) partial agonism. Prototype hybrid molecules were designed using docking to receptor homology models. Diverse pharmacophore moieties yielded 3 series of hybrids with varying in vitro properties at 5-HT6R and D2R, and at M1 receptor and hERG channel antitargets. 4-(piperazin-1-yl)-1H-indole derivatives showed highest antagonist potency at 5-HT6R, with 7-butoxy-3,4-dihydroquinolin-2(1H)-one and 2-propoxybenzamide derivatives having promising D2R partial agonism. 2-(3-(4-(1-(phenylsulfonyl)-1H-indol-4-yl)piperazin-1-yl)propoxy)benzamide (47) exhibited nanomolar affinity at both 5-HT6R and D2R and was evaluated in rat models. It displayed potent antidepressant-like and anxiolytic-like activity in the Porsolt and Vogel tests, respectively, more pronounced than that of a reference selective 5-HT6R antagonist or D2R partial agonist. In addition, 47 also showed antidepressant-like activity (Porsolt's test) and anxiolytic-like activity (open field test) in aged (>18-month old) rats. In operant conditioning tests, 47 enhanced responding for sweet reward in the saccharin self-administration test, consistent with anti-anhedonic properties. Further, 47 facilitated extinction of non-reinforced responding for sweet reward, suggesting potential procognitive activity. Taken together, these studies suggest that DMLs combining 5-HT6R antagonism and D2R partial agonism may successfully target affective disorders in patients from different age groups without a risk of cognitive deficits.
|
Displacement of [3H]pirenzepine from human recombinant muscarinic M1 receptor expressed in CHO cells
|
Homo sapiens
|
21.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, physico-chemical properties and biological evaluation of some new N-[(phenoxy)alkyl]- and N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols as anticonvulsant agents.
Year : 2016
Volume : 24
Issue : 8
First Page : 1793
Last Page : 1810
Authors : Waszkielewicz AM, Gunia-Krzyżak A, Powroźnik B, Słoczyńska K, Pękala E, Walczak M, Bednarski M, Żesławska E, Nitek W, Marona H.
Abstract : A series of thirty N-(phenoxy)alkyl or N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols has been designed, synthesized and evaluated for anticonvulsant activity in MES, 6Hz test, and pilocarpine-induced status epilepticus. Among the title compounds, the most promising seems R-(-)-2N-{2-[2-(2,6-dimethylphenoxy)ethoxy]ethyl}aminopropan-1-ol hydrochloride (22a) with proved absolute configuration with X-ray analysis and enantiomeric purity. The compound is effective in MES test with ED50=12.92 mg/kg b.w. and its rotarod TD50=33.26 mg/kg b.w. The activity dose is also effective in a neurogenic pain model-the formalin test. Within high throughput profile assay, among eighty one targets, the strongest affinity of the compound is observed towards σ receptors and 5-HT transporter and the compound does not bind to hERG. It also does not exhibit mutagenic properties in the Vibrio harveyi test. Moreover, murine liver microsomal assay and pharmacokinetics profile (mice, iv, p.o., ip) indicate that the liver is the primary site of biotransformation of the compound, suggesting that both 22a and its metabolite(s) are active, compensating probably low bioavailability of the parent molecule.
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Displacement of [3H]pirenzepine from human recombinant M1 receptor expressed in CHO cells measured after 60 mins by scintillation counting method
|
Homo sapiens
|
21.0
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-anticonvulsant activity studies in the group of (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3.
Year : 2017
Volume : 25
Issue : 2
First Page : 471
Last Page : 482
Authors : Gunia-Krzyżak A, Żelaszczyk D, Rapacz A, Żesławska E, Waszkielewicz AM, Pańczyk K, Słoczyńska K, Pękala E, Nitek W, Filipek B, Marona H.
Abstract : A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3 was designed, synthesized and evaluated for anticonvulsant activity in rodent models of seizures: maximal electroshock (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and 6-Hz test. There were identified three most active compounds: S-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (5) (ED50 MES=42.56, ED50 scPTZ=58.38, ED50 6-Hz 44mA=42.27mg/kg tested in mice after intraperitoneal (i.p.) administration); R,S-(2E)-3-(4-chlorophenyl)-N-(1-hydroxybutan-2-yl)prop-2-enamide (6) (ED50 MES=53.76, ED50 scPTZ=90.31, ED50 6-Hz 44mA=92.86mg/kg mice, i.p.); and R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide (11) (ED50 MES=55.58, ED50 scPTZ=102.15, ED50 6-Hz 44mA=51.27mg/kg mice, i.p.). Their structures and configurations were confirmed by crystal X-ray diffraction method. The structure-activity studies among the tested series showed that chlorine atom in position para or methyl group in position ortho of phenyl ring were beneficial for anticonvulsant activity. Methyl group in position para of phenyl ring decreased anticonvulsant activity in reported series of cinnamamide derivatives.
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Displacement of [3H]pirenzepine from human recombinant Muscarinic acetylcholine receptor M1 expressed in CHO cells after 60 mins by scintillation counting
|
Homo sapiens
|
27.0
nM
|
|
Displacement of [3H]pirenzepine from human recombinant Muscarinic acetylcholine receptor M1 expressed in CHO cells after 60 mins by scintillation counting
|
Homo sapiens
|
24.0
nM
|
|
Journal : J Med Chem
Title : Pyrimidine-Based Inhibitors of Dynamin I GTPase Activity: Competitive Inhibition at the Pleckstrin Homology Domain.
Year : 2017
Volume : 60
Issue : 1
First Page : 349
Last Page : 361
Authors : Odell LR, Abdel-Hamid MK, Hill TA, Chau N, Young KA, Deane FM, Sakoff JA, Andersson S, Daniel JA, Robinson PJ, McCluskey A.
Abstract : The large GTPase dynamin mediates membrane fission during clathrin-mediated endocytosis (CME). The aminopyrimidine compounds were reported to disrupt dynamin localization to the plasma membrane via the PH domain and implicate this mechanism in the inhibition of CME. We have used a computational approach of binding site identification, docking, and interaction energy calculations to design and synthesize a new library of aminopyrimidine analogues targeting site-2 of the pleckstrin homology (PH) domain. The optimized analogues showed low micromolar inhibition against both dynamin I (IC50 = 10.6 ± 1.3 to 1.6 ± 0.3 μM) and CME (IC50(CME) = 65.9 ± 7.7 to 3.7 ± 1.1 mM), which makes this series among the more potent inhibitors of dynamin and CME yet reported. In CME and growth inhibition cell-based assays, the data obtained was consistent with dynamin inhibition. CEREP ExpresS profiling identified off-target effects at the cholecystokinin, dopamine D2, histamine H1 and H2, melanocortin, melatonin, muscarinic M1 and M3, neurokinin, opioid KOP and serotonin receptors.
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Displacement of [3H]-pyrilamine from human recombinant M1 receptor expressed in CHO cells after 60 mins by scintillation counting
|
Homo sapiens
|
20.0
nM
|
|
Journal : J Med Chem
Title : Novel 3-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-indole-Based Multifunctional Ligands with Antipsychotic-Like, Mood-Modulating, and Procognitive Activity.
Year : 2017
Volume : 60
Issue : 17
First Page : 7483
Last Page : 7501
Authors : Bucki A, Marcinkowska M, Śniecikowska J, Więckowski K, Pawłowski M, Głuch-Lutwin M, Gryboś A, Siwek A, Pytka K, Jastrzębska-Więsek M, Partyka A, Wesołowska A, Mierzejewski P, Kołaczkowski M.
Abstract : The most troublesome aspects of behavioral and psychological symptoms of dementia (BPSD) are nowadays addressed by antidepressant, anxiolytic, and antipsychotic drugs, often administered off-label. Considering their modest effectiveness in dementia patients, the increased risk of adverse events and cognitive decline, there is an unmet need for well-tolerated and effective therapy of BPSD. We designed and synthesized multifunctional ligands characterized in vitro as high-affinity partial agonists of D2R, antagonists of 5-HT6R, and blockers of SERT. Moreover, the molecules activated 5-HT1AR and blocked 5-HT7R while having no relevant affinity for off-target M1R and hERG channel. Compound 16 (N-{2-[4-(5-chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl}-3-methylbenzene-1-sulfonamide) exhibited a broad antipsychotic-, antidepressant-, and anxiolytic-like activity, not eliciting motor impairments in mice. Most importantly, 16 showed memory-enhancing properties and it ameliorated memory deficits induced by scopolamine. The molecule outperformed most important comparators in selected tests, indicating its potential in the treatment of both cognitive and noncognitive (behavioral and psychological) symptoms of dementia.
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SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.1
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.2
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.2
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
