|
Tested for antimuscarinic potency on guinea pig heart force
|
Cavia porcellus
|
1.122
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselectivity of muscarinic antagonists. Isomeric 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl]-1,3-oxathiolane methiodides.
Year : 1988
Volume : 31
Issue : 9
First Page : 1703
Last Page : 1708
Authors : Romanelli MN, Gualtieri F, Valle G, Brasili L, Angeli P.
Abstract : The four isomers of 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl] -1,3-oxathiolane methiodide were prepared. Their absolute configuration was attributed by means of X-ray crystallography and circular dichroism. The compounds were tested on rat bladder and guinea pig ileum and heart, and their antimuscarinic potency was evaluated and expressed as pA2. The results show that the introduction of a chiral center into position 2 brings about a small but definite enantioselectivity on rat bladder and guinea pig ileum which is not seen for guinea pig heart. This supports the view that differences exist among the muscarinic receptors of these tissues (M2 receptors). Comparison of the absolute configuration of the antagonists studied in this and in the preceding paper2 and that of strictly related agonists supports the hypothesis of a common binding site for agonists and antagonists of this kind.
|
Tested for antimuscarinic potency on guinea pig heart rate
|
Cavia porcellus
|
0.8913
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselectivity of muscarinic antagonists. Isomeric 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl]-1,3-oxathiolane methiodides.
Year : 1988
Volume : 31
Issue : 9
First Page : 1703
Last Page : 1708
Authors : Romanelli MN, Gualtieri F, Valle G, Brasili L, Angeli P.
Abstract : The four isomers of 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl] -1,3-oxathiolane methiodide were prepared. Their absolute configuration was attributed by means of X-ray crystallography and circular dichroism. The compounds were tested on rat bladder and guinea pig ileum and heart, and their antimuscarinic potency was evaluated and expressed as pA2. The results show that the introduction of a chiral center into position 2 brings about a small but definite enantioselectivity on rat bladder and guinea pig ileum which is not seen for guinea pig heart. This supports the view that differences exist among the muscarinic receptors of these tissues (M2 receptors). Comparison of the absolute configuration of the antagonists studied in this and in the preceding paper2 and that of strictly related agonists supports the hypothesis of a common binding site for agonists and antagonists of this kind.
|
Tested for antimuscarinic potency on guinea pig ileum
|
Cavia porcellus
|
1.23
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselectivity of muscarinic antagonists. Isomeric 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl]-1,3-oxathiolane methiodides.
Year : 1988
Volume : 31
Issue : 9
First Page : 1703
Last Page : 1708
Authors : Romanelli MN, Gualtieri F, Valle G, Brasili L, Angeli P.
Abstract : The four isomers of 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl] -1,3-oxathiolane methiodide were prepared. Their absolute configuration was attributed by means of X-ray crystallography and circular dichroism. The compounds were tested on rat bladder and guinea pig ileum and heart, and their antimuscarinic potency was evaluated and expressed as pA2. The results show that the introduction of a chiral center into position 2 brings about a small but definite enantioselectivity on rat bladder and guinea pig ileum which is not seen for guinea pig heart. This supports the view that differences exist among the muscarinic receptors of these tissues (M2 receptors). Comparison of the absolute configuration of the antagonists studied in this and in the preceding paper2 and that of strictly related agonists supports the hypothesis of a common binding site for agonists and antagonists of this kind.
|
Tested for antimuscarinic potency on rat bladder
|
Rattus norvegicus
|
1.288
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselectivity of muscarinic antagonists. Isomeric 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl]-1,3-oxathiolane methiodides.
Year : 1988
Volume : 31
Issue : 9
First Page : 1703
Last Page : 1708
Authors : Romanelli MN, Gualtieri F, Valle G, Brasili L, Angeli P.
Abstract : The four isomers of 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl] -1,3-oxathiolane methiodide were prepared. Their absolute configuration was attributed by means of X-ray crystallography and circular dichroism. The compounds were tested on rat bladder and guinea pig ileum and heart, and their antimuscarinic potency was evaluated and expressed as pA2. The results show that the introduction of a chiral center into position 2 brings about a small but definite enantioselectivity on rat bladder and guinea pig ileum which is not seen for guinea pig heart. This supports the view that differences exist among the muscarinic receptors of these tissues (M2 receptors). Comparison of the absolute configuration of the antagonists studied in this and in the preceding paper2 and that of strictly related agonists supports the hypothesis of a common binding site for agonists and antagonists of this kind.
|
Compound was evaluated for the binding affinity by displacing [3H]methylscopolamine [3H]NMS from mouse cerebral cortex tissue.
|
None
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cholinergic properties of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine.
Year : 1992
Volume : 35
Issue : 6
First Page : 1102
Last Page : 1108
Authors : Sowell JW, Tang Y, Valli MJ, Chapman JM, Usher LA, Vaughan CM, Kosh JW.
Abstract : The histaminergic H2 antagonist, ranitidine, has also been found to significantly inhibit acetylcholinesterase (AChE) in vitro. In an effort to develop novel, nonquaternary AChE inhibitors capable of penetrating into the CNS and alleviating the cholinergic deficit characteristic of Alzheimer's disease, a series of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine has been synthesized. All compounds were evaluated for human erythrocyte AChE inhibitory activity and compared to ranitidine, physostigmine, and tetrahydro-9-aminoacridine (THA). The most active AChE inhibitors were N,N'-disubstituted derivatives of 2-nitro-1,1-ethenediamine and 4,6-dinitro-1,3-benzenediamine, with compound 8 demonstrating activity greater than physostigmine. Deletion of the diaminonitroethene group in a series of alkyl and aryl bis-thioethers, yielded a number of slightly less active compounds, comparable in potency to THA. The 13 most active AChE inhibitors all demonstrated a more selective inhibition of AChE, as opposed to butyrylcholinesterase inhibition, than did THA. Compounds 3 and 22 were equally active to THA in potentiating rat ileal contractions. Binding studies demonstrated M1 and M2 cholinergic receptor affinities slightly greater than or equal to THA. Differential receptor binding studies showed compound 12 resembled THA in agonist/antagonist activity. Compounds 11-13 significantly elevated mouse brain acetylcholine levels, when administered at 80% of their approximate lethal doses, but were less active than THA or physostigmine.
|
Compound was evaluated for the binding affinity by displacing [3H]oxotremorine from mouse cerebral cortex tissue.
|
None
|
0.35
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cholinergic properties of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine.
Year : 1992
Volume : 35
Issue : 6
First Page : 1102
Last Page : 1108
Authors : Sowell JW, Tang Y, Valli MJ, Chapman JM, Usher LA, Vaughan CM, Kosh JW.
Abstract : The histaminergic H2 antagonist, ranitidine, has also been found to significantly inhibit acetylcholinesterase (AChE) in vitro. In an effort to develop novel, nonquaternary AChE inhibitors capable of penetrating into the CNS and alleviating the cholinergic deficit characteristic of Alzheimer's disease, a series of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine has been synthesized. All compounds were evaluated for human erythrocyte AChE inhibitory activity and compared to ranitidine, physostigmine, and tetrahydro-9-aminoacridine (THA). The most active AChE inhibitors were N,N'-disubstituted derivatives of 2-nitro-1,1-ethenediamine and 4,6-dinitro-1,3-benzenediamine, with compound 8 demonstrating activity greater than physostigmine. Deletion of the diaminonitroethene group in a series of alkyl and aryl bis-thioethers, yielded a number of slightly less active compounds, comparable in potency to THA. The 13 most active AChE inhibitors all demonstrated a more selective inhibition of AChE, as opposed to butyrylcholinesterase inhibition, than did THA. Compounds 3 and 22 were equally active to THA in potentiating rat ileal contractions. Binding studies demonstrated M1 and M2 cholinergic receptor affinities slightly greater than or equal to THA. Differential receptor binding studies showed compound 12 resembled THA in agonist/antagonist activity. Compounds 11-13 significantly elevated mouse brain acetylcholine levels, when administered at 80% of their approximate lethal doses, but were less active than THA or physostigmine.
|
Evaluated for the inhibition of adenylate cyclase at M2 receptor in rat heart
|
Rattus norvegicus
|
7.5
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.
|
Dissociation constant of the compound-receptor complex.
|
Cavia porcellus
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restricted analogues of the muscarinic agent N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide.
Year : 1989
Volume : 32
Issue : 4
First Page : 863
Last Page : 869
Authors : Lundkvist JR, Ringdahl B, Hacksell U.
Abstract : Conformationally restricted analogues of the selective partial muscarinic agonist N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM 5; 2) were synthesized. The compounds were tested for muscarinic and antimuscarinic activity in the isolated guinea pig ileum and in intact mice. They were found to be moderately potent muscarinic antagonists or weak partial agonists. The new compounds were less potent than 2 in inhibiting (-)-[3H]-N-methylscopolamine binding in the rate cerebral cortex. Thus, structural modifications of 2 in which part of the amide moiety has been connected with the methyl group in the butynyl chain to form a five-membered ring decrease affinity and in most cases abolish efficacy.
|
Anticholinergic activity was determined in vitro by measuring their effect on the acetylcholine chloride induced contraction of guinea pig ileum
|
Cavia porcellus
|
0.0038
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Antisecretory activity of human, dog, and rat metabolites of fenoctimine.
Year : 1987
Volume : 30
Issue : 5
First Page : 894
Last Page : 899
Authors : Scott MK, Jacoby HI, Bonfilio AC, Corcoran TW, Lopez IS.
Abstract : Fenoctimine (1a), a nonanticholinergic inhibitor of gastric acid secretion in dogs and rats, was evaluated as a gastric antisecretory agent in humans. In humans it exhibited weak antisecretory activity and caused anticholinergic-like side effects such as dry mouth and nasal passages. Studies of the metabolic fate of fenoctimine in humans, dogs, and rats provided structures of the resultant metabolites. These were synthesized and tested for antisecretory and anticholinergic activity. The human metabolites were all less active than fenoctimine as antisecretory agents, and some displayed significant anticholinergic activity. These results suggest that the unexpectedly weak effect of fenoctimine as a gastric antisecretory agent in humans, as well as anticholinergic effects, may be due to its extensive metabolism, which is different from that seen in dog and rat.
|
Antimuscarinic activity was assayed for its ability to block the acetyl-choline induced contraction of the guinea pig ileum
|
Cavia porcellus
|
1.995
nM
|
|
Journal : J. Med. Chem.
Title : 6-Methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (azaprophen), a highly potent antimuscarinic agent.
Year : 1987
Volume : 30
Issue : 5
First Page : 805
Last Page : 809
Authors : Carroll FI, Abraham P, Parham K, Griffith RC, Ahmad A, Richard MM, Padilla FN, Witkin JM, Chiang PK.
Abstract : The synthesis and antimuscarinic properties of 6-methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (1, azaprophen) are described. Azaprophen is 50 times more potent than atropine as an antimuscarinic agent as measured by the inhibition of acetylcholine-induced contraction of guinea pig ileum and is more than 1000 times better than atropine in its ability to block alpha-amylase release from pancreatic acini cells induced by carbachol. In addition, azaprophen is 27 times more potent than atropine as an inhibitor of binding of [N-methyl-3H]scopolamine to muscarinic receptors, with human IMR-30 neuroblastoma cells. The potencies of azaprophen and atropine in altering operant behavior were similar. The structural features of 1 are compared to the standard anticholinergic drugs atropine and quinuclidinyl benzilate by using energy calculations and molecular modelling studies. A modification of the pharmacophore model hypothesis for cholinergic agents is suggested.
|
Ability to displace [3H](-)-quinuclidinyl benzilate(QNB) from M2 receptor in rat heart homogenate
|
None
|
0.76
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).
|
Ability to displace [3H]N-methylscopolamine (NMS) from M3 receptor in rat submaxillary gland homogenate
|
None
|
0.12
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).
|
Ability to displace [3H]pirenzepine (PZ) from M1 receptor in rat cortex homogenate
|
None
|
0.26
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).
|
Inhibition of [3H]NMS binding to cerebral cortex membranes which contain predominantly the Muscarinic acetylcholine receptor M1 subtypes
|
None
|
2.4
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.
|
Inhibition of [3H]QNB binding to CHO cells bearing transfected muscarinic acetylcholine receptor M3
|
Cricetulus griseus
|
0.329
nM
|
|
Journal : J. Med. Chem.
Title : Crystal, solution, and molecular modeling structural properties and muscarinic antagonist activity of azaprophen.
Year : 1991
Volume : 34
Issue : 4
First Page : 1436
Last Page : 1440
Authors : Carroll FI, Abraham P, Mascarella SW, Singh P, Moreland CG, Sankar SS, Kwon YW, Triggle DJ.
Abstract : The structure of azaprophen, which was originally assigned by 1H NMR analysis, was confirmed by X-ray crystallography. A comparison of 13C NMR isotropic chemical shift data for azaprophen in the solid state and in CDCl3 and DMSO-d6 solution was used to correlate solution and solid-state conformation as determined by the X-ray data. The data suggested that the solid-state and solution conformation of azaprophen were similar. The observed solid-state structure was also compared to low-energy conformations identified by molecular-mechanics calculations. A comparison of azaprophen and atropine radioligand binding in guinea pig ileum, rat heart, rat brain, and in CHO cells expressing transfected m1 and m3 receptors was conducted. Azaprophen is more active than atropine in all preparations except the m3 receptor expressed in CHO cells. However, like atropine, it does not provide major discrimination among the muscarinic receptor subtypes.
|
Antagonism to the H1 receptor of guinea pig ileum was determined
|
Cavia porcellus
|
0.7762
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, biological in vitro evaluation and stereoselectivity of ondansetron analogues: novel 5-HT2A receptor antagonists
Year : 1995
Volume : 5
Issue : 7
First Page : 667
Last Page : 672
Authors : Elz S, Heil WL
|
Displacement of [3H]QNB from rat ileum Muscarinic acetylcholine receptor
|
Rattus norvegicus
|
0.45
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of some 3-(1-azabicyclo[2.2.2]octyl) 3-amino-2-hydroxy-2-phenylpropionates: profile of antimuscarinic efficacy and selectivity.
Year : 1990
Volume : 33
Issue : 1
First Page : 307
Last Page : 310
Authors : Audia VH, McPherson DW, Weitzberg M, Rzeszotarski WJ, Sturm B, Kachur JF, Abreu M, Kaiser C.
Abstract : A series of 3-quinuclidinyl atrolactate [3-(1-azabicyclo[2.2.2]octyl) 2-hydroxy-2-phenylpropionate, QNA] derivatives in which the methyl group of the parent is substituted with a tertiary amino substituent was prepared and tested for antimuscarinic activity. In general, potency was markedly decreased, although the morpholinyl and thiomorpholinyl derivatives retained significant activity. These compounds were also examined for muscarinic receptor subtype selectivity. Their subtype selectivities were comparable to that of (R,R)-QNA. The results of this investigation suggest possible differences in the accessory binding sites of the proteinaceous receptor subtypes.
|
Inhibition of [3H]QNB binding towards muscarinic acetylcholine receptor in guinea pig ileum.
|
Cavia porcellus
|
0.683
nM
|
|
Journal : J. Med. Chem.
Title : Crystal, solution, and molecular modeling structural properties and muscarinic antagonist activity of azaprophen.
Year : 1991
Volume : 34
Issue : 4
First Page : 1436
Last Page : 1440
Authors : Carroll FI, Abraham P, Mascarella SW, Singh P, Moreland CG, Sankar SS, Kwon YW, Triggle DJ.
Abstract : The structure of azaprophen, which was originally assigned by 1H NMR analysis, was confirmed by X-ray crystallography. A comparison of 13C NMR isotropic chemical shift data for azaprophen in the solid state and in CDCl3 and DMSO-d6 solution was used to correlate solution and solid-state conformation as determined by the X-ray data. The data suggested that the solid-state and solution conformation of azaprophen were similar. The observed solid-state structure was also compared to low-energy conformations identified by molecular-mechanics calculations. A comparison of azaprophen and atropine radioligand binding in guinea pig ileum, rat heart, rat brain, and in CHO cells expressing transfected m1 and m3 receptors was conducted. Azaprophen is more active than atropine in all preparations except the m3 receptor expressed in CHO cells. However, like atropine, it does not provide major discrimination among the muscarinic receptor subtypes.
|
Dissociation constant towards Muscarinic acetylcholine receptor in guinea pig ileum
|
Cavia porcellus
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Resolved pyrrolidine, piperidine, and perhydroazepine analogues of the muscarinic agent N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide.
Year : 1990
Volume : 33
Issue : 12
First Page : 3182
Last Page : 3189
Authors : Lundkvist JR, Vargas HM, Caldirola P, Ringdahl B, Hacksell U.
Abstract : A series of conformationally restricted analogues of the partial muscarinic agonist N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM 5; 1) was synthesized. Three of the racemic derivatives were resolved into the enantiomers. The compounds were investigated for muscarinic and antimuscarinic activity in the isolated guinea pig ileum. They were found to be fairly potent muscarinic antagonists or weak partial agonists. The new compounds were either equally or less potent than 1 in inhibiting (-)-[3H]-N-methylscopolamine binding in homogenates of the rat cerebral cortex. Thus, structural modifications to 1 in which the amide moiety and the methyl group in the butynyl chain have been joined to form a six- or seven-membered ring preserve affinity but abolish efficacy. The R enantiomers were found to have 14-79 times higher affinity to ileal muscarinic receptors than the respective antipodes. The enantiomeric affinity ratios were nearly identical in both preparations studied. As suggested by molecular mechanics calculations, the difference in affinity between the five-membered and the six- and seven-membered ring analogues may be rationalized in conformational terms.
|
Determination of dissociation constant from antimuscarinic activity on isolated guinea pig ileum.
|
Cavia porcellus
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Phenyl-substituted analogues of oxotremorine as muscarinic antagonists.
Year : 1992
Volume : 35
Issue : 2
First Page : 285
Last Page : 294
Authors : Nilsson BM, Vargas HM, Ringdahl B, Hacksell U.
Abstract : A series of phenyl-substituted analogues of the muscarinic agent oxotremorine (1) have been prepared. The new compounds (3b-11b and 9c) were assayed for antimuscarinic activity on the isolated guinea pig ileum and in intact mice. They were also evaluated for ability to inhibit the binding of the muscarinic antagonist (-)-[3H]-N-methylscopolamine to homogenates of the rat cerebral cortex. The phenyl-substituted derivatives were devoid of intrinsic muscarinic activity. Instead, they behaved as competitive muscarinic antagonists in these assays with similar or lower affinity for muscarinic receptors than the corresponding methyl-substituted analogues. The succinimide (8b) and the pyrrolidone (3b) derivatives of 1 substituted with a phenyl group at position 1 of the butynyl chain showed the highest antimuscarinic potency with dissociation constants (KD) of 0.10 and 0.20 microM, respectively, in the ileum assay. The phenyl-substituted analogues showed an approximately 10-fold lower in vivo antimuscarinic potency than their corresponding methyl-substituted positional isomers. A correlation was observed between in vitro and in vivo potency within subsets consisting of methyl- and phenyl-substituted derivatives.
|
Ability of compound to displace (-)-[3H]3-Quinuclidinyl benzilate (-)-[3H]-QNB from Muscarinic acetylcholine receptors in cerebral cortex from Guinea Pig.
|
Cavia porcellus
|
0.32
nM
|
|
Journal : J. Med. Chem.
Title : Antimuscarinic 3-(2-furanyl)quinuclidin-2-ene derivatives: synthesis and structure-activity relationships.
Year : 1997
Volume : 40
Issue : 23
First Page : 3804
Last Page : 3819
Authors : Johansson G, Sundquist S, Nordvall G, Nilsson BM, Brisander M, Nilvebrant L, Hacksell U.
Abstract : A series of 25 derivatives of the muscarinic antagonist 3-(2-furanyl)quinuclidin-2-ene (4) was synthesized and evaluated for muscarinic and antimuscarinic properties. Substitution at all three positions of the furan ring has been investigated. The affinities of the new compounds were determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. Several of the novel derivatives displayed high muscarinic affinities. Whereas the affinity of lead compound 4 for cortical muscarinic receptors is moderate (Ki = 300 nM), it is much higher for the 5-methyl (48; Ki = 12 nM), 5-ethyl (52; Ki = 7.4 nM), 5-bromo (33; Ki = 6.4 nM), and 3-phenyl (49; Ki = 2.8 nM) substituted derivatives. The substituent-induced increases in affinity do not appear to be additive as a 5-bromo-3-phenyl (54), and a 5-methyl-3-phenyl (55) substitution pattern only slightly increases affinity (Ki = 1.55 and 2.39 nM, respectively). The conformational preferences of the 3-phenyl (49) and 5-phenyl (51) derivatives were studied by X-ray crystallography and molecular mechanics calculations. Because of the observed high affinity of 49, a series of 16 meta- and para-substituted analogues of 49 was synthesized and tested. The m-hydroxy derivative (68) exhibited more than 10-fold improvement in affinity as compared to 49. The structure-activity relationships of the new series are well described with QSAR and CoMFA models.
|
Ability of compound to displace (-)-[3H]3-Quinuclidinyl benzilate (-)-[3H]-QNB from Muscarinic acetylcholine receptors in the heart from Guinea Pig.
|
Cavia porcellus
|
0.89
nM
|
|
Journal : J. Med. Chem.
Title : Antimuscarinic 3-(2-furanyl)quinuclidin-2-ene derivatives: synthesis and structure-activity relationships.
Year : 1997
Volume : 40
Issue : 23
First Page : 3804
Last Page : 3819
Authors : Johansson G, Sundquist S, Nordvall G, Nilsson BM, Brisander M, Nilvebrant L, Hacksell U.
Abstract : A series of 25 derivatives of the muscarinic antagonist 3-(2-furanyl)quinuclidin-2-ene (4) was synthesized and evaluated for muscarinic and antimuscarinic properties. Substitution at all three positions of the furan ring has been investigated. The affinities of the new compounds were determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. Several of the novel derivatives displayed high muscarinic affinities. Whereas the affinity of lead compound 4 for cortical muscarinic receptors is moderate (Ki = 300 nM), it is much higher for the 5-methyl (48; Ki = 12 nM), 5-ethyl (52; Ki = 7.4 nM), 5-bromo (33; Ki = 6.4 nM), and 3-phenyl (49; Ki = 2.8 nM) substituted derivatives. The substituent-induced increases in affinity do not appear to be additive as a 5-bromo-3-phenyl (54), and a 5-methyl-3-phenyl (55) substitution pattern only slightly increases affinity (Ki = 1.55 and 2.39 nM, respectively). The conformational preferences of the 3-phenyl (49) and 5-phenyl (51) derivatives were studied by X-ray crystallography and molecular mechanics calculations. Because of the observed high affinity of 49, a series of 16 meta- and para-substituted analogues of 49 was synthesized and tested. The m-hydroxy derivative (68) exhibited more than 10-fold improvement in affinity as compared to 49. The structure-activity relationships of the new series are well described with QSAR and CoMFA models.
|
Ability of compound to displace (-)-[3H]3-Quinuclidinyl benzilate (-)-[3H]-QNB from Muscarinic acetylcholine receptors in the parotid gland from Guinea Pig.
|
Cavia porcellus
|
0.85
nM
|
|
Journal : J. Med. Chem.
Title : Antimuscarinic 3-(2-furanyl)quinuclidin-2-ene derivatives: synthesis and structure-activity relationships.
Year : 1997
Volume : 40
Issue : 23
First Page : 3804
Last Page : 3819
Authors : Johansson G, Sundquist S, Nordvall G, Nilsson BM, Brisander M, Nilvebrant L, Hacksell U.
Abstract : A series of 25 derivatives of the muscarinic antagonist 3-(2-furanyl)quinuclidin-2-ene (4) was synthesized and evaluated for muscarinic and antimuscarinic properties. Substitution at all three positions of the furan ring has been investigated. The affinities of the new compounds were determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. Several of the novel derivatives displayed high muscarinic affinities. Whereas the affinity of lead compound 4 for cortical muscarinic receptors is moderate (Ki = 300 nM), it is much higher for the 5-methyl (48; Ki = 12 nM), 5-ethyl (52; Ki = 7.4 nM), 5-bromo (33; Ki = 6.4 nM), and 3-phenyl (49; Ki = 2.8 nM) substituted derivatives. The substituent-induced increases in affinity do not appear to be additive as a 5-bromo-3-phenyl (54), and a 5-methyl-3-phenyl (55) substitution pattern only slightly increases affinity (Ki = 1.55 and 2.39 nM, respectively). The conformational preferences of the 3-phenyl (49) and 5-phenyl (51) derivatives were studied by X-ray crystallography and molecular mechanics calculations. Because of the observed high affinity of 49, a series of 16 meta- and para-substituted analogues of 49 was synthesized and tested. The m-hydroxy derivative (68) exhibited more than 10-fold improvement in affinity as compared to 49. The structure-activity relationships of the new series are well described with QSAR and CoMFA models.
|
Affinity for Muscarinic acetylcholine receptors in urinary bladder from Guinea Pig by (-)-[3H]3-Quinuclidinyl benzilate (-)-[3H]-QNB displacement.
|
Cavia porcellus
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Antimuscarinic 3-(2-furanyl)quinuclidin-2-ene derivatives: synthesis and structure-activity relationships.
Year : 1997
Volume : 40
Issue : 23
First Page : 3804
Last Page : 3819
Authors : Johansson G, Sundquist S, Nordvall G, Nilsson BM, Brisander M, Nilvebrant L, Hacksell U.
Abstract : A series of 25 derivatives of the muscarinic antagonist 3-(2-furanyl)quinuclidin-2-ene (4) was synthesized and evaluated for muscarinic and antimuscarinic properties. Substitution at all three positions of the furan ring has been investigated. The affinities of the new compounds were determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. Several of the novel derivatives displayed high muscarinic affinities. Whereas the affinity of lead compound 4 for cortical muscarinic receptors is moderate (Ki = 300 nM), it is much higher for the 5-methyl (48; Ki = 12 nM), 5-ethyl (52; Ki = 7.4 nM), 5-bromo (33; Ki = 6.4 nM), and 3-phenyl (49; Ki = 2.8 nM) substituted derivatives. The substituent-induced increases in affinity do not appear to be additive as a 5-bromo-3-phenyl (54), and a 5-methyl-3-phenyl (55) substitution pattern only slightly increases affinity (Ki = 1.55 and 2.39 nM, respectively). The conformational preferences of the 3-phenyl (49) and 5-phenyl (51) derivatives were studied by X-ray crystallography and molecular mechanics calculations. Because of the observed high affinity of 49, a series of 16 meta- and para-substituted analogues of 49 was synthesized and tested. The m-hydroxy derivative (68) exhibited more than 10-fold improvement in affinity as compared to 49. The structure-activity relationships of the new series are well described with QSAR and CoMFA models.
|
Inhibition of [3H]NMS (N-[3H]methylscopolamine) binding to Muscarinic acetylcholine receptor (mAChR)
|
Cavia porcellus
|
2.4
nM
|
|
Journal : J. Med. Chem.
Title : Pyridophens: binary pyridostigmine-aprophen prodrugs with differential inhibition of acetylcholinesterase, butyrylcholinesterase, and muscarinic receptors.
Year : 2002
Volume : 45
Issue : 4
First Page : 902
Last Page : 910
Authors : Leader H, Wolfe AD, Chiang PK, Gordon RK.
Abstract : A series of "binary prodrugs" called carbaphens,(1) carbamylated derivatives on one or both of the aromatic rings of the muscarinic receptor antagonist aprophen [(N,N-diethylamino)ethyl 2,2-diphenylpropionate], were synthesized to develop binary prophylactic agents against organophosphorus intoxication. As a group, the carbaphens retained the muscarinic receptor antagonist properties of aprophen but also preferentially inhibited butyrylcholinesterase (BChE) in contrast to acetylcholinesterase (AChE). Therefore, a new series of compounds named pyridophens were designed and synthesized to achieve binary prodrugs to preferentially inhibit AChE over BChE, while still retaining the muscarinic receptor antagonism of aprophen. The pyridophens consist of the basic pyridostigmine skeleton combined with the 2,2-diphenylpropionate portion of aprophen by replacement of the diethylamino group. Three compounds, 9 (a tertiary pyridine), 10 (a quaternary pyridine), and 12 (a tertiary tetrahydropyridine), were found to be effective inhibitors of both BChE and AChE. However, 10, N-methyl-3-[[(dimethylamino)carbonyl]oxy]-2-(2'2'-diphenylpropionoxy-methyl)pyridinium iodide, inhibited AChE selectively over BChE, with a bimolecular rate constant similar to pyridostigmine. In contrast to their potent cholinesterase inhibitory activity, all of the pyridophen analogues were less potent antagonists of the muscarinic receptor than aprophen.
|
Binding affinity (Ki) against binding of [3H]NMS using membranes from CHO cells expressing cloned human Muscarinic acetylcholine receptor M1
|
Homo sapiens
|
0.25
nM
|
|
Journal : J. Med. Chem.
Title : Cyclohexylmethylpiperidinyltriphenylpropioamide: a selective muscarinic M(3) antagonist discriminating against the other receptor subtypes.
Year : 2002
Volume : 45
Issue : 4
First Page : 984
Last Page : 987
Authors : Sagara Y, Sagara T, Mase T, Kimura T, Numazawa T, Fujikawa T, Noguchi K, Ohtake N.
Abstract : To discover a highly selective M(3) antagonist, a combinatorial library was prepared. The library was designed to identify a novel structural class of M(3) antagonists by exploring the spatial arrangement of the pharmacophores in known M(3) antagonists. After the evaluation of 1000 library members, a potent M(3) antagonist, 14a (K(i) = 0.31 nM), with novel structural features was identified. Compound 14a showed high selectivity for M(3) receptors over the other muscarinic receptor subtypes (M(1)/M(3) = 380-fold, M(2)/M(3) = 98-fold, M(4)/M(3) = 45-fold, M(5)/M(3) = 120-fold).
|
Antagonist activity against Muscarinic acetylcholine receptor of guinea pig heart.
|
Cavia porcellus
|
1.122
nM
|
|
Antagonist activity against Muscarinic acetylcholine receptor of guinea pig heart.
|
Cavia porcellus
|
0.8913
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselectivity of muscarinic antagonists. 2,2-Dicyclohexyl-5-[(dimethylamino)methyl]-1,3-oxathiolane methiodides and related 3-oxides.
Year : 1988
Volume : 31
Issue : 9
First Page : 1698
Last Page : 1702
Authors : Romanelli MN, Teodori E, Gualtieri F, Angeli P, Brasili L.
Abstract : The enantiomers of three chiral muscarinic antagonists carrying a 1,3-oxathiolane nucleus were prepared and their absolute configuration established. The enantioselectivity and tissue selectivity of such compounds were studied on rat bladder and guinea pig ileum and heart. The results show that introduction of a sulfoxide function brings about a small but definite enantioselectivity in the 1,3-oxathiolane compound (2), which in itself does not show enantioselectivity among the tissues studied. The results obtained point to differences among cardiac and ileal muscarinic receptors. Comparison of the absolute configuration related agonists shows that the most potent isomers of both series share the same absolute stereochemistry.
|
Antagonist activity against Muscarinic acetylcholine receptor of guinea pig ileum
|
Cavia porcellus
|
1.23
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselectivity of muscarinic antagonists. 2,2-Dicyclohexyl-5-[(dimethylamino)methyl]-1,3-oxathiolane methiodides and related 3-oxides.
Year : 1988
Volume : 31
Issue : 9
First Page : 1698
Last Page : 1702
Authors : Romanelli MN, Teodori E, Gualtieri F, Angeli P, Brasili L.
Abstract : The enantiomers of three chiral muscarinic antagonists carrying a 1,3-oxathiolane nucleus were prepared and their absolute configuration established. The enantioselectivity and tissue selectivity of such compounds were studied on rat bladder and guinea pig ileum and heart. The results show that introduction of a sulfoxide function brings about a small but definite enantioselectivity in the 1,3-oxathiolane compound (2), which in itself does not show enantioselectivity among the tissues studied. The results obtained point to differences among cardiac and ileal muscarinic receptors. Comparison of the absolute configuration related agonists shows that the most potent isomers of both series share the same absolute stereochemistry.
|
Antagonist potency against muscarinic receptors was assed by antagonism of carbachol induced inhibition of electrically stimulated guinea pig atria
|
Cavia porcellus
|
1.349
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships among methoctramine-related polymethylene tetraamines. Chain-length and substituent effects on M-2 muscarinic receptor blocking activity.
Year : 1989
Volume : 32
Issue : 1
First Page : 79
Last Page : 84
Authors : Melchiorre C, Quaglia W, Picchio MT, Giardinà D, Brasili L, Angeli P.
Abstract : Several polymethylene tetraamines related to methoctramine (1) were prepared and evaluated for their blocking activity on M-2 muscarinic receptors in guinea pig atria and ileum. It turned out that antimuscarinic potency depends on the following parameters: (a) nature of the substituent on both inner and outer nitrogens and (b) carbon chain length separating the inner nitrogens as well as the inner and outer nitrogens. Optimum activity at cardiac M-2 muscarinic receptors was associated with the chain lengths present in 1, that is, eight methylenes between the inner nitrogens and six methylenes between the inner and outer nitrogens. With regard to the substituents, replacement of the benzylic moiety of 1 by a 2-furyl or a 5-methyl-2-furyl nucleus resulted in enhanced potency toward cardiac M-2 muscarinic receptors. In fact, furtramine (18) and mefurtramine (19) proved to be more potent and more selective than 1. Moreover, N-methylation of the four nitrogens of 1 gave different effects: methylation of the outer nitrogens, giving 22, caused a significant decrease in activity whereas methylation of the inner nitrogens, yielding 23, resulted in an increase in activity in both atria and ileum.
|
Antagonist potency against carbachol induced contractions of isolated guinea pig ileum Muscarinic acetylcholine receptor
|
Cavia porcellus
|
1.479
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships among methoctramine-related polymethylene tetraamines. Chain-length and substituent effects on M-2 muscarinic receptor blocking activity.
Year : 1989
Volume : 32
Issue : 1
First Page : 79
Last Page : 84
Authors : Melchiorre C, Quaglia W, Picchio MT, Giardinà D, Brasili L, Angeli P.
Abstract : Several polymethylene tetraamines related to methoctramine (1) were prepared and evaluated for their blocking activity on M-2 muscarinic receptors in guinea pig atria and ileum. It turned out that antimuscarinic potency depends on the following parameters: (a) nature of the substituent on both inner and outer nitrogens and (b) carbon chain length separating the inner nitrogens as well as the inner and outer nitrogens. Optimum activity at cardiac M-2 muscarinic receptors was associated with the chain lengths present in 1, that is, eight methylenes between the inner nitrogens and six methylenes between the inner and outer nitrogens. With regard to the substituents, replacement of the benzylic moiety of 1 by a 2-furyl or a 5-methyl-2-furyl nucleus resulted in enhanced potency toward cardiac M-2 muscarinic receptors. In fact, furtramine (18) and mefurtramine (19) proved to be more potent and more selective than 1. Moreover, N-methylation of the four nitrogens of 1 gave different effects: methylation of the outer nitrogens, giving 22, caused a significant decrease in activity whereas methylation of the inner nitrogens, yielding 23, resulted in an increase in activity in both atria and ileum.
|
Compound was evaluated for blocking activity on Muscarinic acetylcholine receptor in guinea pig atria
|
Cavia porcellus
|
2.042
nM
|
|
Journal : J. Med. Chem.
Title : Differential blockade of muscarinic receptor subtypes by polymethylene tetraamines. Novel class of selective antagonists of cardiac M-2 muscarinic receptors.
Year : 1987
Volume : 30
Issue : 1
First Page : 201
Last Page : 204
Authors : Melchiorre C, Cassinelli A, Quaglia W.
Abstract : Several N,N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1, omega-alkanediamine tetrahydrochlorides were synthesized and evaluated for their blocking activity on muscarinic receptors in guinea pig atria and rat ileum and bladder. The results were compared with those obtained for the classical nonselective muscarinic antagonist atropine. It was discovered that optimum activity is associated with an eight-carbon chain (compound 4) in guinea pig atria whereas, in both rat ileum and bladder, the 12-carbon analogue 7 had the highest activity. In addition, polymethylene tetraamines 1-6 displayed high selectivity toward guinea pig atria muscarinic receptors. The discriminatory power of 1-6 was not shared by 7. All the tetraamines were shown to be competitive antagonists of muscarinic receptors. N,N'-Bis[6-[(2-methoxybenzyl)amino]hexyl]-1,8-octanediamine was the most potent and selective toward muscarinic receptors in atria, with a pA2 value of 8.13 and a selectivity ratio (atria vs. ileum or bladder) of ca. 270. At a concentration of 10 microM, tetraamine 4 did not affect histamine and 5-hydroxytryptamine receptors of guinea pig ileum or alpha-adrenoreceptors of guinea pig atria whereas it inhibited postsynaptic alpha-adrenoreceptors of rat vas deferens with a -log K value of 5.23 and nicotinic receptors of frog rectus abdominis with an IC50 value of 0.23 microM. It is concluded that 4 is a novel, powerful, and selective tool in the characterization of muscarinic receptor subtypes.
|
muscarinic acetylcholine receptor M1
|
Cricetulus griseus
|
0.344
nM
|
|
Journal : J. Med. Chem.
Title : Crystal, solution, and molecular modeling structural properties and muscarinic antagonist activity of azaprophen.
Year : 1991
Volume : 34
Issue : 4
First Page : 1436
Last Page : 1440
Authors : Carroll FI, Abraham P, Mascarella SW, Singh P, Moreland CG, Sankar SS, Kwon YW, Triggle DJ.
Abstract : The structure of azaprophen, which was originally assigned by 1H NMR analysis, was confirmed by X-ray crystallography. A comparison of 13C NMR isotropic chemical shift data for azaprophen in the solid state and in CDCl3 and DMSO-d6 solution was used to correlate solution and solid-state conformation as determined by the X-ray data. The data suggested that the solid-state and solution conformation of azaprophen were similar. The observed solid-state structure was also compared to low-energy conformations identified by molecular-mechanics calculations. A comparison of azaprophen and atropine radioligand binding in guinea pig ileum, rat heart, rat brain, and in CHO cells expressing transfected m1 and m3 receptors was conducted. Azaprophen is more active than atropine in all preparations except the m3 receptor expressed in CHO cells. However, like atropine, it does not provide major discrimination among the muscarinic receptor subtypes.
|
Inhibit the binding of [N-mnethyl-3H]-scopolamine [3H]-NMS) to Muscarinic acetylcholine receptor of human IRM-30 neuroblastoma cells
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : 6-Methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (azaprophen), a highly potent antimuscarinic agent.
Year : 1987
Volume : 30
Issue : 5
First Page : 805
Last Page : 809
Authors : Carroll FI, Abraham P, Parham K, Griffith RC, Ahmad A, Richard MM, Padilla FN, Witkin JM, Chiang PK.
Abstract : The synthesis and antimuscarinic properties of 6-methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (1, azaprophen) are described. Azaprophen is 50 times more potent than atropine as an antimuscarinic agent as measured by the inhibition of acetylcholine-induced contraction of guinea pig ileum and is more than 1000 times better than atropine in its ability to block alpha-amylase release from pancreatic acini cells induced by carbachol. In addition, azaprophen is 27 times more potent than atropine as an inhibitor of binding of [N-methyl-3H]scopolamine to muscarinic receptors, with human IMR-30 neuroblastoma cells. The potencies of azaprophen and atropine in altering operant behavior were similar. The structural features of 1 are compared to the standard anticholinergic drugs atropine and quinuclidinyl benzilate by using energy calculations and molecular modelling studies. A modification of the pharmacophore model hypothesis for cholinergic agents is suggested.
|
Binding affinity (Ki) against binding of [3H]NMS using membranes from CHO cells expressing cloned human Muscarinic acetylcholine receptor M3
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Cyclohexylmethylpiperidinyltriphenylpropioamide: a selective muscarinic M(3) antagonist discriminating against the other receptor subtypes.
Year : 2002
Volume : 45
Issue : 4
First Page : 984
Last Page : 987
Authors : Sagara Y, Sagara T, Mase T, Kimura T, Numazawa T, Fujikawa T, Noguchi K, Ohtake N.
Abstract : To discover a highly selective M(3) antagonist, a combinatorial library was prepared. The library was designed to identify a novel structural class of M(3) antagonists by exploring the spatial arrangement of the pharmacophores in known M(3) antagonists. After the evaluation of 1000 library members, a potent M(3) antagonist, 14a (K(i) = 0.31 nM), with novel structural features was identified. Compound 14a showed high selectivity for M(3) receptors over the other muscarinic receptor subtypes (M(1)/M(3) = 380-fold, M(2)/M(3) = 98-fold, M(4)/M(3) = 45-fold, M(5)/M(3) = 120-fold).
|
Concentration of compound for 50% displacement of [3H]QNB from Muscarinic acetylcholine receptor in rat brain
|
None
|
4.84
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restricted tricyclic antidepressants. 1. Octahydrodibenzazepinonaphthyridines as rigid imipramine analogues.
Year : 1980
Volume : 23
Issue : 8
First Page : 865
Last Page : 873
Authors : Martin AR, Paradkar VM, Peng GW, Speth RC, Yamamura HI, Horn AS.
|
In vitro receptor binding against Muscarinic acetylcholine receptor M3 in rat submandibular gland was determined using [3H]pirenzepine
|
Rattus norvegicus
|
0.63
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of new antimuscarinic compounds with amidine basic centers. A useful bioisosteric replacement of classical cationic heads.
Year : 1990
Volume : 33
Issue : 8
First Page : 2108
Last Page : 2113
Authors : Cereda E, Ezhaya A, Gil Quintero M, Bellora E, Dubini E, Micheletti R, Schiavone A, Brambilla A, Schiavi GB, Donetti A.
Abstract : Amidines (guanidine, formamidine, and acetamidine) were introduced as substitutes for the cationic heads present in atropine, scopolamine, and corresponding quaternary derivatives. Amidine systems are intermediate in structure between tertiary amines and quaternary compounds, at least as regards ionization and electronic properties, but differ from the latter in shape (planar not tetrahedral). They have additional binding opportunities on account of their hydrogen-bond-forming capacity. The effect of the introduction of these cationic heads on the affinity for different muscarinic acetyl choline receptor (m-AcChR) subtypes was investigated in vitro, in binding displacement studies, and in functional tests on isolated organs. All new compounds (3a,b-5a,b) showed high affinity for the m-AcChR considered, comparable or slightly inferior to that of the parent drugs (1a-e). The new amidine derivatives proved effective as spasmolytic agents, with little tendency to cause central effects. However, no separation was achieved of spasmolytic and other untoward effects, like inhibition of salivation. Thus, amidine moieties are effective bioisosteric substitutes for conventional cationic heads present in antimuscarinic agents. Their unusual physical-chemical properties make them useful tools when modulation of pharmacokinetic or pharmacodynamic effects is required.
|
In vitro receptor binding against Muscarinic acetylcholine receptor M1 in rat cerebral cortex was determined using [3H]pirenzepine
|
Rattus norvegicus
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of new antimuscarinic compounds with amidine basic centers. A useful bioisosteric replacement of classical cationic heads.
Year : 1990
Volume : 33
Issue : 8
First Page : 2108
Last Page : 2113
Authors : Cereda E, Ezhaya A, Gil Quintero M, Bellora E, Dubini E, Micheletti R, Schiavone A, Brambilla A, Schiavi GB, Donetti A.
Abstract : Amidines (guanidine, formamidine, and acetamidine) were introduced as substitutes for the cationic heads present in atropine, scopolamine, and corresponding quaternary derivatives. Amidine systems are intermediate in structure between tertiary amines and quaternary compounds, at least as regards ionization and electronic properties, but differ from the latter in shape (planar not tetrahedral). They have additional binding opportunities on account of their hydrogen-bond-forming capacity. The effect of the introduction of these cationic heads on the affinity for different muscarinic acetyl choline receptor (m-AcChR) subtypes was investigated in vitro, in binding displacement studies, and in functional tests on isolated organs. All new compounds (3a,b-5a,b) showed high affinity for the m-AcChR considered, comparable or slightly inferior to that of the parent drugs (1a-e). The new amidine derivatives proved effective as spasmolytic agents, with little tendency to cause central effects. However, no separation was achieved of spasmolytic and other untoward effects, like inhibition of salivation. Thus, amidine moieties are effective bioisosteric substitutes for conventional cationic heads present in antimuscarinic agents. Their unusual physical-chemical properties make them useful tools when modulation of pharmacokinetic or pharmacodynamic effects is required.
|
Displacement of [3H]pirenzepine from muscarinic acetylcholine receptor M1 in rat cortex homogenates
|
Rattus norvegicus
|
0.26
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).
|
Binding affinity (Ki) against binding of [3H]NMS using membranes from CHO cells expressing cloned human Muscarinic acetylcholine receptor M4
|
Homo sapiens
|
0.34
nM
|
|
Journal : J. Med. Chem.
Title : Cyclohexylmethylpiperidinyltriphenylpropioamide: a selective muscarinic M(3) antagonist discriminating against the other receptor subtypes.
Year : 2002
Volume : 45
Issue : 4
First Page : 984
Last Page : 987
Authors : Sagara Y, Sagara T, Mase T, Kimura T, Numazawa T, Fujikawa T, Noguchi K, Ohtake N.
Abstract : To discover a highly selective M(3) antagonist, a combinatorial library was prepared. The library was designed to identify a novel structural class of M(3) antagonists by exploring the spatial arrangement of the pharmacophores in known M(3) antagonists. After the evaluation of 1000 library members, a potent M(3) antagonist, 14a (K(i) = 0.31 nM), with novel structural features was identified. Compound 14a showed high selectivity for M(3) receptors over the other muscarinic receptor subtypes (M(1)/M(3) = 380-fold, M(2)/M(3) = 98-fold, M(4)/M(3) = 45-fold, M(5)/M(3) = 120-fold).
|
Inhibition of [3H]- Oxo-M binding to muscarinic acetylcholine receptor of rat brain membrane preparations
|
None
|
0.459
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and muscarinic receptor activity of ester derivatives of 2-substituted 2-azabicyclo[2.2.1]heptan-5-ol and -6-ol.
Year : 1992
Volume : 35
Issue : 12
First Page : 2184
Last Page : 2191
Authors : Carroll FI, Abraham P, Chemburkar S, He XC, Mascarella SW, Kwon YW, Triggle DJ.
Abstract : Radioligand binding affinities of four new muscarinic antagonists and six potential muscarinic agonists which possess the 2-alkyl-2-azabicyclo[2.2.1]heptane ring system have been determined in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations to examine the selectivity for subtypes of muscarinic receptor. The efficacies of the potential muscarinic agonists were determined by the ratio of binding affinities against [3H]QNB and [3H]Oxo-M. Four muscarinic antagonists which have the 2,2-diphenylpropionate side chain at either the C5 (5-endo or 5-exo) or the C6 (6-endo or 6-exo) positions did not discriminate between the subtypes of muscarinic receptors. The 2,2-diphenylpropionate 5-endo substituted compound was the most potent, showing affinities between 4.23 x 10(-10) and 1.18 x 10(-9) M in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations. The rank order of ester potency was 5-endo greater than 5-exo greater than 6-endo greater than 6-exo. A molecular modeling study based on the pharmacophore developed for azaprophen was used to account for the relative potency of these antagonists. Six potential muscarinic agonists which have acetoxy groups in the C5 or C6 position with an N-methyl or N-benzyl substituent did not discriminate subtypes of muscarinic receptors and had affinities between 6.63 x 10(-6) and 4.76 x 10(-5) M in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations. exo-2-Methyl-5-acetoxy-2-azabicyclo[2.2.1]heptane was the most efficacious partial agonist.
|
Inhibition of [3H]QNB binding to muscarinic acetylcholine receptor of rat heart membrane preparation.
|
None
|
0.337
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and muscarinic receptor activity of ester derivatives of 2-substituted 2-azabicyclo[2.2.1]heptan-5-ol and -6-ol.
Year : 1992
Volume : 35
Issue : 12
First Page : 2184
Last Page : 2191
Authors : Carroll FI, Abraham P, Chemburkar S, He XC, Mascarella SW, Kwon YW, Triggle DJ.
Abstract : Radioligand binding affinities of four new muscarinic antagonists and six potential muscarinic agonists which possess the 2-alkyl-2-azabicyclo[2.2.1]heptane ring system have been determined in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations to examine the selectivity for subtypes of muscarinic receptor. The efficacies of the potential muscarinic agonists were determined by the ratio of binding affinities against [3H]QNB and [3H]Oxo-M. Four muscarinic antagonists which have the 2,2-diphenylpropionate side chain at either the C5 (5-endo or 5-exo) or the C6 (6-endo or 6-exo) positions did not discriminate between the subtypes of muscarinic receptors. The 2,2-diphenylpropionate 5-endo substituted compound was the most potent, showing affinities between 4.23 x 10(-10) and 1.18 x 10(-9) M in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations. The rank order of ester potency was 5-endo greater than 5-exo greater than 6-endo greater than 6-exo. A molecular modeling study based on the pharmacophore developed for azaprophen was used to account for the relative potency of these antagonists. Six potential muscarinic agonists which have acetoxy groups in the C5 or C6 position with an N-methyl or N-benzyl substituent did not discriminate subtypes of muscarinic receptors and had affinities between 6.63 x 10(-6) and 4.76 x 10(-5) M in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations. exo-2-Methyl-5-acetoxy-2-azabicyclo[2.2.1]heptane was the most efficacious partial agonist.
|
The compound was tested for inhibition of [3H]NMS binding against muscarinic acetylcholine receptor in rat brain
|
None
|
0.3
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, molecular modeling studies, and muscarinic receptor activity of azaprophen analogues.
Year : 1991
Volume : 34
Issue : 11
First Page : 3164
Last Page : 3171
Authors : Triggle DJ, Kwon YW, Abraham P, Pitner JB, Mascarella SW, Carroll FI.
Abstract : Synthesis, radioligand binding, and pharmacologic activities of a series of muscarinic receptor ligands including and related to azaprophen (6-methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate, 1) have been measured to determine activity and selectivity for muscarinic receptor subtypes. Pharmacologic affinities of antagonists were determined as pA2 values for antagonism of methacholine-induced tension responses in guinea pig ileum. Binding affinities were measured by competition against [3H]QNB binding in guinea pig ileum, rat heart and brain, and m1- or m3-transfected Chinese hamster ovary (CHO) cells. The efficacies of muscarinic agonists in brain were determined by the ratio of binding affinities against [3H]QNB or [3H]NMS and [3H]oxotremorine-M ([3H]Oxo-M). Nine muscarinic antagonists, including azaprophen, did not discriminate significantly between the subtypes of muscarinic receptors. KI values for receptor binding for azaprophen (1) were between 8.81 x 10(-11) and 4.72 x 10(-10) M in ileum, heart, brain, and m1- or m3-transfected CHO cells. The alpha- and beta-benzilate esters 5 and 6 are as potent as azaprophen, and diphenylacetate esters 3 and 4 and N-(6)-benzyl alpha-isomer 7 are less potent than azaprophen. Significant stereoselectivity was exhibited with (+)-azaprophen being approximately 200 times more potent than the (-)-enantiomers and the 3 beta-ol isomer 2 being ca. 50 times less potent than azaprophen in all systems. A molecular modeling-molecular mechanics study was conducted to account for the difference. Putative muscarinic agonists (analogues and isomers of 6-methyl-6-azabicyclo[3.2.1]octan-3-ol acetate) did not discriminate muscarinic receptor subtypes with KI values between 2.77 x 10(-6) and 4.33 x 10(-5) M without significant stereoselectivity in the systems examined. The most active analogue was (1R,3R,5S)-6-[1(R)-phenylethyl]-6-azabicyclo[3.2.1]octan-3 alpha-ol acetate. However, efficacies of these putative agonists were in general very low.
|
Inhibition of [3H]QNB binding against muscarinic acetylcholine receptor in rat brain.
|
None
|
0.337
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, molecular modeling studies, and muscarinic receptor activity of azaprophen analogues.
Year : 1991
Volume : 34
Issue : 11
First Page : 3164
Last Page : 3171
Authors : Triggle DJ, Kwon YW, Abraham P, Pitner JB, Mascarella SW, Carroll FI.
Abstract : Synthesis, radioligand binding, and pharmacologic activities of a series of muscarinic receptor ligands including and related to azaprophen (6-methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate, 1) have been measured to determine activity and selectivity for muscarinic receptor subtypes. Pharmacologic affinities of antagonists were determined as pA2 values for antagonism of methacholine-induced tension responses in guinea pig ileum. Binding affinities were measured by competition against [3H]QNB binding in guinea pig ileum, rat heart and brain, and m1- or m3-transfected Chinese hamster ovary (CHO) cells. The efficacies of muscarinic agonists in brain were determined by the ratio of binding affinities against [3H]QNB or [3H]NMS and [3H]oxotremorine-M ([3H]Oxo-M). Nine muscarinic antagonists, including azaprophen, did not discriminate significantly between the subtypes of muscarinic receptors. KI values for receptor binding for azaprophen (1) were between 8.81 x 10(-11) and 4.72 x 10(-10) M in ileum, heart, brain, and m1- or m3-transfected CHO cells. The alpha- and beta-benzilate esters 5 and 6 are as potent as azaprophen, and diphenylacetate esters 3 and 4 and N-(6)-benzyl alpha-isomer 7 are less potent than azaprophen. Significant stereoselectivity was exhibited with (+)-azaprophen being approximately 200 times more potent than the (-)-enantiomers and the 3 beta-ol isomer 2 being ca. 50 times less potent than azaprophen in all systems. A molecular modeling-molecular mechanics study was conducted to account for the difference. Putative muscarinic agonists (analogues and isomers of 6-methyl-6-azabicyclo[3.2.1]octan-3-ol acetate) did not discriminate muscarinic receptor subtypes with KI values between 2.77 x 10(-6) and 4.33 x 10(-5) M without significant stereoselectivity in the systems examined. The most active analogue was (1R,3R,5S)-6-[1(R)-phenylethyl]-6-azabicyclo[3.2.1]octan-3 alpha-ol acetate. However, efficacies of these putative agonists were in general very low.
|
Inhibition of [3H]OXO-M binding against muscarinic acetylcholine receptor in rat brain membranes
|
None
|
0.459
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, molecular modeling studies, and muscarinic receptor activity of azaprophen analogues.
Year : 1991
Volume : 34
Issue : 11
First Page : 3164
Last Page : 3171
Authors : Triggle DJ, Kwon YW, Abraham P, Pitner JB, Mascarella SW, Carroll FI.
Abstract : Synthesis, radioligand binding, and pharmacologic activities of a series of muscarinic receptor ligands including and related to azaprophen (6-methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate, 1) have been measured to determine activity and selectivity for muscarinic receptor subtypes. Pharmacologic affinities of antagonists were determined as pA2 values for antagonism of methacholine-induced tension responses in guinea pig ileum. Binding affinities were measured by competition against [3H]QNB binding in guinea pig ileum, rat heart and brain, and m1- or m3-transfected Chinese hamster ovary (CHO) cells. The efficacies of muscarinic agonists in brain were determined by the ratio of binding affinities against [3H]QNB or [3H]NMS and [3H]oxotremorine-M ([3H]Oxo-M). Nine muscarinic antagonists, including azaprophen, did not discriminate significantly between the subtypes of muscarinic receptors. KI values for receptor binding for azaprophen (1) were between 8.81 x 10(-11) and 4.72 x 10(-10) M in ileum, heart, brain, and m1- or m3-transfected CHO cells. The alpha- and beta-benzilate esters 5 and 6 are as potent as azaprophen, and diphenylacetate esters 3 and 4 and N-(6)-benzyl alpha-isomer 7 are less potent than azaprophen. Significant stereoselectivity was exhibited with (+)-azaprophen being approximately 200 times more potent than the (-)-enantiomers and the 3 beta-ol isomer 2 being ca. 50 times less potent than azaprophen in all systems. A molecular modeling-molecular mechanics study was conducted to account for the difference. Putative muscarinic agonists (analogues and isomers of 6-methyl-6-azabicyclo[3.2.1]octan-3-ol acetate) did not discriminate muscarinic receptor subtypes with KI values between 2.77 x 10(-6) and 4.33 x 10(-5) M without significant stereoselectivity in the systems examined. The most active analogue was (1R,3R,5S)-6-[1(R)-phenylethyl]-6-azabicyclo[3.2.1]octan-3 alpha-ol acetate. However, efficacies of these putative agonists were in general very low.
|
Antimuscarinic activity on the acetylcholine-induced inhibition of contraction of guinea pig ileum which has M2 muscarinic receptor subtype.
|
Cavia porcellus
|
1.995
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 (Ki) against binding of [3H]NMS using membranes from CHO cells expressing cloned human Muscarinic acetylcholine receptor M5
|
Homo sapiens
|
0.54
nM
|
|
Journal : J. Med. Chem.
Title : Cyclohexylmethylpiperidinyltriphenylpropioamide: a selective muscarinic M(3) antagonist discriminating against the other receptor subtypes.
Year : 2002
Volume : 45
Issue : 4
First Page : 984
Last Page : 987
Authors : Sagara Y, Sagara T, Mase T, Kimura T, Numazawa T, Fujikawa T, Noguchi K, Ohtake N.
Abstract : To discover a highly selective M(3) antagonist, a combinatorial library was prepared. The library was designed to identify a novel structural class of M(3) antagonists by exploring the spatial arrangement of the pharmacophores in known M(3) antagonists. After the evaluation of 1000 library members, a potent M(3) antagonist, 14a (K(i) = 0.31 nM), with novel structural features was identified. Compound 14a showed high selectivity for M(3) receptors over the other muscarinic receptor subtypes (M(1)/M(3) = 380-fold, M(2)/M(3) = 98-fold, M(4)/M(3) = 45-fold, M(5)/M(3) = 120-fold).
|
Binding affinity against Muscarinic acetylcholine receptors using [3H]oxotremorine-M as radioligand in rat cortex
|
None
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Muscarinic analgesics with potent and selective effects on the gastrointestinal tract: potential application for the treatment of irritable bowel syndrome.
Year : 1997
Volume : 40
Issue : 4
First Page : 538
Last Page : 546
Authors : Mitch CH, Brown TJ, Bymaster FP, Calligaro DO, Dieckman D, Merrit L, Peters SC, Quimby SJ, Shannon HE, Shipley LA, Ward JS, Hansen K, Olesen PH, Sauerberg P, Sheardown MJ, Swedberg MD, Suzdak P, Greenwood B.
Abstract : Irritable bowel syndrome (IBS) is a pathopysiolocal condition characterized by abnormal bowel habits that are frequently accompanied by abdominal pain. Current therapy based on reducing high-amplitude GI contractions with nonselective muscarinic antagonists is limited in efficacy due to typical muscarinic side effects and provides no pain relief. We have previously found potent antinociceptive agents acting through muscarinic receptors. In the present work, new 1,2,5-thiadiazole-based structures with muscarinic activity have been evaluated both for activity as analgesics in the mouse withing assay and for activity in normalizing spontaneous cluster contractions in ferret jejunum as a model of IBS in humans. (5R,6R)-exo-6-[4-[(4,4,4-Trifluorobutyl)thio]-1,2,5-thiadiazol+ ++-3-yl] -1-azabicyclo[3.2.1]octane (35, LY316108/NNC11-2192) was found to offer an exceptional profile combining analgesic potency in mouse writhing (ED50 = 0.1 mg/kg) along with potency for normalization of GI motility (ED50 = 0.17 mg/kg). This combination of GI and analgesic potency suggests 35 as an excellent candidate for evaluation as a potential treatment of IBS.
|
Antagonist activity against Muscarinic acetylcholine receptor of rat bladder
|
Rattus norvegicus
|
1.288
nM
|
|
Journal : J. Med. Chem.
Title : Enantioselectivity of muscarinic antagonists. 2,2-Dicyclohexyl-5-[(dimethylamino)methyl]-1,3-oxathiolane methiodides and related 3-oxides.
Year : 1988
Volume : 31
Issue : 9
First Page : 1698
Last Page : 1702
Authors : Romanelli MN, Teodori E, Gualtieri F, Angeli P, Brasili L.
Abstract : The enantiomers of three chiral muscarinic antagonists carrying a 1,3-oxathiolane nucleus were prepared and their absolute configuration established. The enantioselectivity and tissue selectivity of such compounds were studied on rat bladder and guinea pig ileum and heart. The results show that introduction of a sulfoxide function brings about a small but definite enantioselectivity in the 1,3-oxathiolane compound (2), which in itself does not show enantioselectivity among the tissues studied. The results obtained point to differences among cardiac and ileal muscarinic receptors. Comparison of the absolute configuration related agonists shows that the most potent isomers of both series share the same absolute stereochemistry.
|
Compound was evaluated for blocking activity on Muscarinic acetylcholine receptor in rat bladder
|
None
|
1.479
nM
|
|
Journal : J. Med. Chem.
Title : Differential blockade of muscarinic receptor subtypes by polymethylene tetraamines. Novel class of selective antagonists of cardiac M-2 muscarinic receptors.
Year : 1987
Volume : 30
Issue : 1
First Page : 201
Last Page : 204
Authors : Melchiorre C, Cassinelli A, Quaglia W.
Abstract : Several N,N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1, omega-alkanediamine tetrahydrochlorides were synthesized and evaluated for their blocking activity on muscarinic receptors in guinea pig atria and rat ileum and bladder. The results were compared with those obtained for the classical nonselective muscarinic antagonist atropine. It was discovered that optimum activity is associated with an eight-carbon chain (compound 4) in guinea pig atria whereas, in both rat ileum and bladder, the 12-carbon analogue 7 had the highest activity. In addition, polymethylene tetraamines 1-6 displayed high selectivity toward guinea pig atria muscarinic receptors. The discriminatory power of 1-6 was not shared by 7. All the tetraamines were shown to be competitive antagonists of muscarinic receptors. N,N'-Bis[6-[(2-methoxybenzyl)amino]hexyl]-1,8-octanediamine was the most potent and selective toward muscarinic receptors in atria, with a pA2 value of 8.13 and a selectivity ratio (atria vs. ileum or bladder) of ca. 270. At a concentration of 10 microM, tetraamine 4 did not affect histamine and 5-hydroxytryptamine receptors of guinea pig ileum or alpha-adrenoreceptors of guinea pig atria whereas it inhibited postsynaptic alpha-adrenoreceptors of rat vas deferens with a -log K value of 5.23 and nicotinic receptors of frog rectus abdominis with an IC50 value of 0.23 microM. It is concluded that 4 is a novel, powerful, and selective tool in the characterization of muscarinic receptor subtypes.
|
Compound was evaluated for blocking activity on Muscarinic acetylcholine receptor in rat ileum
|
None
|
1.318
nM
|
|
Journal : J. Med. Chem.
Title : Differential blockade of muscarinic receptor subtypes by polymethylene tetraamines. Novel class of selective antagonists of cardiac M-2 muscarinic receptors.
Year : 1987
Volume : 30
Issue : 1
First Page : 201
Last Page : 204
Authors : Melchiorre C, Cassinelli A, Quaglia W.
Abstract : Several N,N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1, omega-alkanediamine tetrahydrochlorides were synthesized and evaluated for their blocking activity on muscarinic receptors in guinea pig atria and rat ileum and bladder. The results were compared with those obtained for the classical nonselective muscarinic antagonist atropine. It was discovered that optimum activity is associated with an eight-carbon chain (compound 4) in guinea pig atria whereas, in both rat ileum and bladder, the 12-carbon analogue 7 had the highest activity. In addition, polymethylene tetraamines 1-6 displayed high selectivity toward guinea pig atria muscarinic receptors. The discriminatory power of 1-6 was not shared by 7. All the tetraamines were shown to be competitive antagonists of muscarinic receptors. N,N'-Bis[6-[(2-methoxybenzyl)amino]hexyl]-1,8-octanediamine was the most potent and selective toward muscarinic receptors in atria, with a pA2 value of 8.13 and a selectivity ratio (atria vs. ileum or bladder) of ca. 270. At a concentration of 10 microM, tetraamine 4 did not affect histamine and 5-hydroxytryptamine receptors of guinea pig ileum or alpha-adrenoreceptors of guinea pig atria whereas it inhibited postsynaptic alpha-adrenoreceptors of rat vas deferens with a -log K value of 5.23 and nicotinic receptors of frog rectus abdominis with an IC50 value of 0.23 microM. It is concluded that 4 is a novel, powerful, and selective tool in the characterization of muscarinic receptor subtypes.
|
Affinity for the Muscarinic acetylcholine receptor
|
Rattus norvegicus
|
1.862
nM
|
|
Journal : J. Med. Chem.
Title : Molecular modification of anticholinergics as probes for muscarinic receptors. 1. Amino esters of alpha-substituted phenylacetic acid and related analogues.
Year : 1987
Volume : 30
Issue : 2
First Page : 273
Last Page : 278
Authors : Lu MC, Wung WE, Shih LB, Callejas S, Gearien JE, Thompson EB.
Abstract : Two series of compounds having the general structure of C6H5CRR'COOCH2CH2NEt2 were synthesized and examined for their antispasmodic activities. These compounds were selected as structural probes for exploring the nature of muscarinic cholinergic receptor binding sites that interact with atropine-like anticholinergics. These studies indicate a rather strict size limitation for the hydrophobic region of the receptor and suggest intramolecular hydrogen bonding as a possible means to explain the observed stereoselectivity.
|
Displacement of [3H]- quinuclidinyl benzilate from rat brain Muscarinic acetylcholine receptor
|
Rattus norvegicus
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : 4-(Diphenylmethyl)-1-[(imino)methyl]piperidines as gastric antisecretory agents.
Year : 1983
Volume : 26
Issue : 4
First Page : 535
Last Page : 538
Authors : Scott MK, Jacoby HI, Mills JE, Bonfilio AC, Rasmussen CR.
Abstract : 4-(Diphenylmethyl)-1-piperidinemethanimine (1) is a potent oral gastric antisecretory agent in rats but contains a strong anticholinergic component. Since a nonanticholinergic gastric antisecretory drug would be useful in the treatment of peptic ulcer disease, a program was initiated by us to find such an agent based on 1. Compound 1 contains structural elements common to the anticholinergics atropine and homatropine. Studies on the structure-activity relationships of these compounds and their derivatives have revealed certain modifications that diminish or abolish anticholinergic activity. The application of these modifications to the design of analogues of 1 afforded an antisecretory compound, 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine (3h, fenoctimine), which exhibited no anticholinergic activity. Fenoctimine is undergoing clinical trial as a gastric antisecretory drug.
|
Inhibition of [3H]QNB binding towards muscarinic acetylcholine receptor in rat brain
|
None
|
0.834
nM
|
|
Journal : J. Med. Chem.
Title : Crystal, solution, and molecular modeling structural properties and muscarinic antagonist activity of azaprophen.
Year : 1991
Volume : 34
Issue : 4
First Page : 1436
Last Page : 1440
Authors : Carroll FI, Abraham P, Mascarella SW, Singh P, Moreland CG, Sankar SS, Kwon YW, Triggle DJ.
Abstract : The structure of azaprophen, which was originally assigned by 1H NMR analysis, was confirmed by X-ray crystallography. A comparison of 13C NMR isotropic chemical shift data for azaprophen in the solid state and in CDCl3 and DMSO-d6 solution was used to correlate solution and solid-state conformation as determined by the X-ray data. The data suggested that the solid-state and solution conformation of azaprophen were similar. The observed solid-state structure was also compared to low-energy conformations identified by molecular-mechanics calculations. A comparison of azaprophen and atropine radioligand binding in guinea pig ileum, rat heart, rat brain, and in CHO cells expressing transfected m1 and m3 receptors was conducted. Azaprophen is more active than atropine in all preparations except the m3 receptor expressed in CHO cells. However, like atropine, it does not provide major discrimination among the muscarinic receptor subtypes.
|
Inhibition of [3H]QNB binding towards muscarinic acetylcholine receptor in rat heart
|
None
|
0.371
nM
|
|
Journal : J. Med. Chem.
Title : Crystal, solution, and molecular modeling structural properties and muscarinic antagonist activity of azaprophen.
Year : 1991
Volume : 34
Issue : 4
First Page : 1436
Last Page : 1440
Authors : Carroll FI, Abraham P, Mascarella SW, Singh P, Moreland CG, Sankar SS, Kwon YW, Triggle DJ.
Abstract : The structure of azaprophen, which was originally assigned by 1H NMR analysis, was confirmed by X-ray crystallography. A comparison of 13C NMR isotropic chemical shift data for azaprophen in the solid state and in CDCl3 and DMSO-d6 solution was used to correlate solution and solid-state conformation as determined by the X-ray data. The data suggested that the solid-state and solution conformation of azaprophen were similar. The observed solid-state structure was also compared to low-energy conformations identified by molecular-mechanics calculations. A comparison of azaprophen and atropine radioligand binding in guinea pig ileum, rat heart, rat brain, and in CHO cells expressing transfected m1 and m3 receptors was conducted. Azaprophen is more active than atropine in all preparations except the m3 receptor expressed in CHO cells. However, like atropine, it does not provide major discrimination among the muscarinic receptor subtypes.
|
Inhibition of [3H]pirenzepine binding towards muscarinic acetylcholine receptor in rat brain.
|
None
|
0.545
nM
|
|
Journal : J. Med. Chem.
Title : Crystal, solution, and molecular modeling structural properties and muscarinic antagonist activity of azaprophen.
Year : 1991
Volume : 34
Issue : 4
First Page : 1436
Last Page : 1440
Authors : Carroll FI, Abraham P, Mascarella SW, Singh P, Moreland CG, Sankar SS, Kwon YW, Triggle DJ.
Abstract : The structure of azaprophen, which was originally assigned by 1H NMR analysis, was confirmed by X-ray crystallography. A comparison of 13C NMR isotropic chemical shift data for azaprophen in the solid state and in CDCl3 and DMSO-d6 solution was used to correlate solution and solid-state conformation as determined by the X-ray data. The data suggested that the solid-state and solution conformation of azaprophen were similar. The observed solid-state structure was also compared to low-energy conformations identified by molecular-mechanics calculations. A comparison of azaprophen and atropine radioligand binding in guinea pig ileum, rat heart, rat brain, and in CHO cells expressing transfected m1 and m3 receptors was conducted. Azaprophen is more active than atropine in all preparations except the m3 receptor expressed in CHO cells. However, like atropine, it does not provide major discrimination among the muscarinic receptor subtypes.
|
Binding affinity (Ki) against binding of [3H]NMS to membranes from CHO cells expressing cloned human Muscarinic acetylcholine receptor M2
|
Homo sapiens
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : Cyclohexylmethylpiperidinyltriphenylpropioamide: a selective muscarinic M(3) antagonist discriminating against the other receptor subtypes.
Year : 2002
Volume : 45
Issue : 4
First Page : 984
Last Page : 987
Authors : Sagara Y, Sagara T, Mase T, Kimura T, Numazawa T, Fujikawa T, Noguchi K, Ohtake N.
Abstract : To discover a highly selective M(3) antagonist, a combinatorial library was prepared. The library was designed to identify a novel structural class of M(3) antagonists by exploring the spatial arrangement of the pharmacophores in known M(3) antagonists. After the evaluation of 1000 library members, a potent M(3) antagonist, 14a (K(i) = 0.31 nM), with novel structural features was identified. Compound 14a showed high selectivity for M(3) receptors over the other muscarinic receptor subtypes (M(1)/M(3) = 380-fold, M(2)/M(3) = 98-fold, M(4)/M(3) = 45-fold, M(5)/M(3) = 120-fold).
|
Binding affinity towards muscarinic m1 receptor
|
None
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 1-phenylcycloalkanecarboxylic acid derivatives are potent and selective sigma 1 ligands.
Year : 1994
Volume : 37
Issue : 15
First Page : 2285
Last Page : 2291
Authors : Calderon SN, Izenwasser S, Heller B, Gutkind JS, Mattson MV, Su TP, Newman AH.
Abstract : Carbetapentane (1, 2-[2-(diethylamino)ethoxy]ethyl 1-phenyl-1-cyclopentanecarboxylate) binds with high affinity to sigma sites and is a potent antitussive, anticonvulsant, and spasmolytic agent. However, carbetapentane interacts at muscarinic binding sites as well, and it is not clear whether either of these receptor systems is involved in the mechanism(s) of action(s) of this drug. In an attempt to determine whether these psychoactivities can be attributed to interaction at sigma sites, a series of carbetapentane analogs were prepared. Phenyl ring substitution; contraction, expansion, and replacement with a methyl group of the cyclopentyl ring; replacement of the carboxylate function with an amide, methyl ether, and methylamine; and replacement of the N,N-diethyl substituent with a morpholino or piperidino moiety were investigated. All of these novel analogs were evaluated for binding to sigma 1 and sigma 2 sites, and comparison of binding at muscarinic m1 and m2 and PCP (1-(1-phenylcyclohexyl)piperidine) receptors was performed. All of the compounds were selective for sigma 1 over sigma 2 sites, with the three most selective analogs being compounds 34 (65-fold), 35 (78-fold), and 39 (51-fold). None of the compounds were active at PCP sites, and chemical modification including (1) replacing the ester function, (2) replacing the cyclopentyl ring with a smaller ring system (cyclopropyl) or a methyl group, and (3) replacing the diethylamino moiety with a morpholino group resulted in > 220-fold selectivity over muscarinic receptor binding. Therefore, several of these novel compounds are potent, sigma 1-selective ligands which can now be investigated as potential antitussive, anticonvulsant, and antiischemic agents. These studies may reveal whether sigma 1 sites play a role in the pharmacological actions of these drugs.
|
Ability to displace [3H]methylscopolamine ([3H]NMS) from mouse cerebral cortex
|
Mus musculus
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cholinergic properties of N-aryl-2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamino analogs of ranitidine.
Year : 1992
Volume : 35
Issue : 17
First Page : 3141
Last Page : 3147
Authors : Valli MJ, Tang Y, Kosh JW, Chapman JM, Sowell JW.
Abstract : A series of N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamino analogs of the H2-antagonist, ranitidine, was synthesized and the abilities of the compounds to alleviate the cholinergic deficit characteristic of Alzheimer's disease evaluated. The compounds were initially tested for their ability to inhibit human erythrocyte acetylcholinesterase activity in vitro. Selected compounds were further evaluated for butyrylcholinesterase inhibition, M1 and M2 cholinergic receptor binding, potentiation of ileal contractions, and the ability to elevate brain acetylcholine levels in mice. The analogs were compared to tetrahydroaminoacridine and to a recently reported series of bis-[[(dimethylamino)methyl]furans]. The N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamine derivatives were generally comparable to tetrahydroaminoacridine and the bis[[(dimethylamino)methyl]furans] in acetylcholinesterase inhibition, M1/M2 receptor binding, and the potentiation of ileal contractions, while being more potent inhibitors of acetylcholinesterase than butyrylcholinesterase. The 4-nitro-3-pyridazinyl analog, 26, was notable in demonstrating a potent and selective binding to the M2 receptor, with an M2 IC50/M1 IC50 of 0.060. Compounds in which the substituents on the dinitro-N-aryl moiety were relatively small were the best at inhibiting acetylcholinesterase in vitro. The N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamines in general, and those with small N-aryl substituents in particular, were superior to the bis[[(dimethylamino)methyl]furans] in elevating brain ACh levels in mice, probably due to enhanced distribution into the CNS. The 1,5-difluoro-2,4-dinitrophenyl analog, 8, resulted in the largest elevation in brain acetylcholine levels, affording a 53% increase at 88 mg/kg.
|
Ability to displace [3H]oxotremorine ([3H]-OXO-M) from mouse cerebral cortex
|
Mus musculus
|
0.35
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cholinergic properties of N-aryl-2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamino analogs of ranitidine.
Year : 1992
Volume : 35
Issue : 17
First Page : 3141
Last Page : 3147
Authors : Valli MJ, Tang Y, Kosh JW, Chapman JM, Sowell JW.
Abstract : A series of N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamino analogs of the H2-antagonist, ranitidine, was synthesized and the abilities of the compounds to alleviate the cholinergic deficit characteristic of Alzheimer's disease evaluated. The compounds were initially tested for their ability to inhibit human erythrocyte acetylcholinesterase activity in vitro. Selected compounds were further evaluated for butyrylcholinesterase inhibition, M1 and M2 cholinergic receptor binding, potentiation of ileal contractions, and the ability to elevate brain acetylcholine levels in mice. The analogs were compared to tetrahydroaminoacridine and to a recently reported series of bis-[[(dimethylamino)methyl]furans]. The N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamine derivatives were generally comparable to tetrahydroaminoacridine and the bis[[(dimethylamino)methyl]furans] in acetylcholinesterase inhibition, M1/M2 receptor binding, and the potentiation of ileal contractions, while being more potent inhibitors of acetylcholinesterase than butyrylcholinesterase. The 4-nitro-3-pyridazinyl analog, 26, was notable in demonstrating a potent and selective binding to the M2 receptor, with an M2 IC50/M1 IC50 of 0.060. Compounds in which the substituents on the dinitro-N-aryl moiety were relatively small were the best at inhibiting acetylcholinesterase in vitro. The N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamines in general, and those with small N-aryl substituents in particular, were superior to the bis[[(dimethylamino)methyl]furans] in elevating brain ACh levels in mice, probably due to enhanced distribution into the CNS. The 1,5-difluoro-2,4-dinitrophenyl analog, 8, resulted in the largest elevation in brain acetylcholine levels, affording a 53% increase at 88 mg/kg.
|
Binding affinity towards muscarinic m2 receptor
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 1-phenylcycloalkanecarboxylic acid derivatives are potent and selective sigma 1 ligands.
Year : 1994
Volume : 37
Issue : 15
First Page : 2285
Last Page : 2291
Authors : Calderon SN, Izenwasser S, Heller B, Gutkind JS, Mattson MV, Su TP, Newman AH.
Abstract : Carbetapentane (1, 2-[2-(diethylamino)ethoxy]ethyl 1-phenyl-1-cyclopentanecarboxylate) binds with high affinity to sigma sites and is a potent antitussive, anticonvulsant, and spasmolytic agent. However, carbetapentane interacts at muscarinic binding sites as well, and it is not clear whether either of these receptor systems is involved in the mechanism(s) of action(s) of this drug. In an attempt to determine whether these psychoactivities can be attributed to interaction at sigma sites, a series of carbetapentane analogs were prepared. Phenyl ring substitution; contraction, expansion, and replacement with a methyl group of the cyclopentyl ring; replacement of the carboxylate function with an amide, methyl ether, and methylamine; and replacement of the N,N-diethyl substituent with a morpholino or piperidino moiety were investigated. All of these novel analogs were evaluated for binding to sigma 1 and sigma 2 sites, and comparison of binding at muscarinic m1 and m2 and PCP (1-(1-phenylcyclohexyl)piperidine) receptors was performed. All of the compounds were selective for sigma 1 over sigma 2 sites, with the three most selective analogs being compounds 34 (65-fold), 35 (78-fold), and 39 (51-fold). None of the compounds were active at PCP sites, and chemical modification including (1) replacing the ester function, (2) replacing the cyclopentyl ring with a smaller ring system (cyclopropyl) or a methyl group, and (3) replacing the diethylamino moiety with a morpholino group resulted in > 220-fold selectivity over muscarinic receptor binding. Therefore, several of these novel compounds are potent, sigma 1-selective ligands which can now be investigated as potential antitussive, anticonvulsant, and antiischemic agents. These studies may reveal whether sigma 1 sites play a role in the pharmacological actions of these drugs.
|
Binding affinity against Muscarinic acetylcholine receptor M1 by displacement of [3H]pirenzepine in bovine striatum
|
Bos taurus
|
0.2
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.
|
In vitro receptor binding against Muscarinic acetylcholine receptor M2 in rat heart was determined using [3H]pirenzepine
|
Rattus norvegicus
|
2.7
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of new antimuscarinic compounds with amidine basic centers. A useful bioisosteric replacement of classical cationic heads.
Year : 1990
Volume : 33
Issue : 8
First Page : 2108
Last Page : 2113
Authors : Cereda E, Ezhaya A, Gil Quintero M, Bellora E, Dubini E, Micheletti R, Schiavone A, Brambilla A, Schiavi GB, Donetti A.
Abstract : Amidines (guanidine, formamidine, and acetamidine) were introduced as substitutes for the cationic heads present in atropine, scopolamine, and corresponding quaternary derivatives. Amidine systems are intermediate in structure between tertiary amines and quaternary compounds, at least as regards ionization and electronic properties, but differ from the latter in shape (planar not tetrahedral). They have additional binding opportunities on account of their hydrogen-bond-forming capacity. The effect of the introduction of these cationic heads on the affinity for different muscarinic acetyl choline receptor (m-AcChR) subtypes was investigated in vitro, in binding displacement studies, and in functional tests on isolated organs. All new compounds (3a,b-5a,b) showed high affinity for the m-AcChR considered, comparable or slightly inferior to that of the parent drugs (1a-e). The new amidine derivatives proved effective as spasmolytic agents, with little tendency to cause central effects. However, no separation was achieved of spasmolytic and other untoward effects, like inhibition of salivation. Thus, amidine moieties are effective bioisosteric substitutes for conventional cationic heads present in antimuscarinic agents. Their unusual physical-chemical properties make them useful tools when modulation of pharmacokinetic or pharmacodynamic effects is required.
|
Binding affinity against Muscarinic acetylcholine receptor M2 by displacement of [3H]QNB in rat myocardium
|
Rattus norvegicus
|
0.7
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
|
0.76
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 carbachol-induced release of alpha-amylase from pancreatic acinar cells from that of rat ileum contained the M2 receptor subtypes
|
None
|
1.6
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.
|
Inhibition of carbachol-induced release of alpha-amylase from pancreatic acini from rat was determined
|
Rattus norvegicus
|
51.0
nM
|
|
Journal : J. Med. Chem.
Title : 6-Methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (azaprophen), a highly potent antimuscarinic agent.
Year : 1987
Volume : 30
Issue : 5
First Page : 805
Last Page : 809
Authors : Carroll FI, Abraham P, Parham K, Griffith RC, Ahmad A, Richard MM, Padilla FN, Witkin JM, Chiang PK.
Abstract : The synthesis and antimuscarinic properties of 6-methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (1, azaprophen) are described. Azaprophen is 50 times more potent than atropine as an antimuscarinic agent as measured by the inhibition of acetylcholine-induced contraction of guinea pig ileum and is more than 1000 times better than atropine in its ability to block alpha-amylase release from pancreatic acini cells induced by carbachol. In addition, azaprophen is 27 times more potent than atropine as an inhibitor of binding of [N-methyl-3H]scopolamine to muscarinic receptors, with human IMR-30 neuroblastoma cells. The potencies of azaprophen and atropine in altering operant behavior were similar. The structural features of 1 are compared to the standard anticholinergic drugs atropine and quinuclidinyl benzilate by using energy calculations and molecular modelling studies. A modification of the pharmacophore model hypothesis for cholinergic agents is suggested.
|
Antispasmodic activity was measured as percent reduction in rat ileum contraction against 300 ug/mL barium chloride 0.5 ug/mL (1.5 X 10E-6 uM)
|
Rattus norvegicus
|
5.9
%
|
|
Journal : J. Med. Chem.
Title : Molecular modification of anticholinergics as probes for muscarinic receptors. 2. Amino esters of alpha-methyltropic acid.
Year : 1987
Volume : 30
Issue : 2
First Page : 424
Last Page : 427
Authors : Lu MC, Shih LB, Jae HS, Gearien JE, Thompson EB.
Abstract : As a continuation of our goals to study molecular probes for muscarinic cholinergic receptors, a series of 3-substituted 2-methyl-2-phenylpropanoates with the general structure of C6H5C(CH2X)(CH3)COOCH2CH2NEt2 where X = OH, OTs, F, Cl, Br, I, and OAc were prepared and their antispasmodic activities examined on isolated rat ileum preparations. Structure-activity relationship studies with these compounds provide further evidence suggesting that binding of an aromatic moiety in a specific location within the hydrophobic region of the receptor is important for anticholinergic potency. A nucleophilic displacement of chloride by "naked" fluoride under mild conditions is also reported.
|
Evaluated for the phosphatidyl inositol turnover at Muscarinic acetylcholine receptor M1 in rat cortex
|
Rattus norvegicus
|
0.5
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.
|
Antispasmodic activity calculated as ability of compound to block ACh-induced contractions of the ileum and expressed as pA2
|
Rattus norvegicus
|
1.862
nM
|
|
Journal : J. Med. Chem.
Title : Molecular modification of anticholinergics as probes for muscarinic receptors. 2. Amino esters of alpha-methyltropic acid.
Year : 1987
Volume : 30
Issue : 2
First Page : 424
Last Page : 427
Authors : Lu MC, Shih LB, Jae HS, Gearien JE, Thompson EB.
Abstract : As a continuation of our goals to study molecular probes for muscarinic cholinergic receptors, a series of 3-substituted 2-methyl-2-phenylpropanoates with the general structure of C6H5C(CH2X)(CH3)COOCH2CH2NEt2 where X = OH, OTs, F, Cl, Br, I, and OAc were prepared and their antispasmodic activities examined on isolated rat ileum preparations. Structure-activity relationship studies with these compounds provide further evidence suggesting that binding of an aromatic moiety in a specific location within the hydrophobic region of the receptor is important for anticholinergic potency. A nucleophilic displacement of chloride by "naked" fluoride under mild conditions is also reported.
|
Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex at 10 uM
|
Cavia porcellus
|
4.5
%
|
|
Journal : J. Med. Chem.
Title : [3H]Batrachotoxinin A 20 alpha-benzoate binding to voltage-sensitive sodium channels: a rapid and quantitative assay for local anesthetic activity in a variety of drugs.
Year : 1985
Volume : 28
Issue : 3
First Page : 381
Last Page : 388
Authors : McNeal ET, Lewandowski GA, Daly JW, Creveling CR.
Abstract : [3H]Batrachotoxinin A benzoate ( [3H]BTX-B) binds with high affinity to sites on voltage-dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex. In this preparation, local anesthetics competitively antagonize the binding of [3H]BTX-B. The potencies of some 40 classical local anesthetics and a variety of catecholamine, histamine, serotonin, adenosine, GABA, glycine, acetylcholine, and calcium antagonists, tranquilizers, antidepressants, barbiturates, anticonvulsants, steroids, vasodilators, antiinflammatories, anticoagulants, analgesics, and other agents have been determined. An excellent correlation with the known local anesthetic activity of many of these agents indicate that antagonism of binding of [3H]BTX-B binding provides a rapid, quantitative, and facile method for the screening and investigation of local anesthetic activity.
|
Inhibition of acetylcholine-induced contraction in guinea pig ileum preincubated for 5 mins before acetylcholine challenge
|
Cavia porcellus
|
2.042
nM
|
|
Journal : J. Nat. Prod.
Title : In vitro study of the anticholinergic and antihistaminic activities of protopine and some derivatives.
Year : 1988
Volume : 51
Issue : 5
First Page : 1021
Last Page : 1022
Authors : Ustünes L, Laekeman GM, Gözler B, Vlietinck AJ, Ozer A, Herman AG.
|
Inhibition of COX2 at 100 uM by scintillation proximity assay
|
None
|
30.0
%
|
|
Journal : J. Nat. Prod.
Title : Screening of ubiquitous plant constituents for COX-2 inhibition with a scintillation proximity based assay.
Year : 2002
Volume : 65
Issue : 11
First Page : 1517
Last Page : 1521
Authors : Huss U, Ringbom T, Perera P, Bohlin L, Vasänge M.
Abstract : A rapid semi-homogeneous cyclooxygenase-2 (COX-2) enzymatic assay using scintillation proximity assay (SPA) technology was developed, and 49 ubiquitous plant secondary metabolites were screened for inhibition of COX-2-catalyzed prostaglandin E(2) (PGE(2)) biosynthesis. Assay conditions were optimized with respect to reaction time, amount of antibody, radiolabeled PGE(2), and SPA beads, and the kinetic parameter, K(m), was estimated. The assay was validated with two natural triterpenoids, ursolic and oleanolic acid, known to inhibit COX-2, as well as with four synthetic COX inhibitors, NS-398, rofecoxib, indomethacin, and aspirin. Plant metabolites of different biosynthetic origin representing several substance classes, including alkaloids, anthraquinones, flavonoids, phenylpropanes, steroids, and terpenes, were screened for inhibition of COX-2-catalyzed PGE(2) production. Of these 49 plant metabolites, eugenol, pyrogallol, and cinnamaldehyde (with IC(50) values of 129, 144, and 245 microM, respectively) were found to inhibit COX-2. This study showed that a COX-2-catalyzed PGE(2) assay using SPA is suitable for screening natural compounds with respect to COX-2 inhibition.
|
Displacement of [3H]pirenzepine from muscarinic M1 receptor
|
None
|
0.3
nM
|
|
Journal : J. Nat. Prod.
Title : The role of receptor binding in drug discovery.
Year : 1993
Volume : 56
Issue : 4
First Page : 441
Last Page : 455
Authors : Sweetnam PM, Caldwell L, Lancaster J, Bauer C, McMillan B, Kinnier WJ, Price CH.
Abstract : Radioligand receptor binding has been used extensively to identify and characterize a host of receptors and enzymes targeting virtually every therapeutic area. Many drug discovery programs have been based on the utilization of radioligand receptor binding technology to identify lead compounds which interact with receptors likely to be important in neuronal, immunological, gastrointestinal, and cardiovascular function/dysfunction. There are several obvious advantages to using in vitro receptor binding as a first level screen when compared to in vivo pharmacometric screens. Scientifically, the structure activity data generated in binding assays is a direct reflection of the ligand/receptor interaction minus the complications which result from secondary events, bioavailability, and pharmacodynamic issues. Technically, the binding studies require only a small amount of test compound (< or = 1 mg), while whole animal studies routinely need gram quantities. Similarly, only a small amount of tissue is required, compared with the cost of purchase and maintenance of live animals for in vivo screening. Supply and labor costs are drastically reduced due to the limited volume and test tube based technology of receptor binding. For these reasons receptor binding assays have been utilized with considerable success to discover site specific lead compounds in virtually every therapeutic area.
|
Activation of human muscarinic M5 receptor expressed in CHO cells coexpressing Gq protein assessed as increase in acetylcholine potency at 30 uM by calcium mobilization-based ACh concentration-response curve assay relative to control
|
Homo sapiens
|
0.21
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins.
Year : 2009
Volume : 52
Issue : 11
First Page : 3445
Last Page : 3448
Authors : Bridges TM, Marlo JE, Niswender CM, Jones CK, Jadhav SB, Gentry PR, Plumley HC, Weaver CD, Conn PJ, Lindsley CW.
Abstract : This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca(2+) mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC(50) of approximately 1.16 microM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
76.5
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Antagonist activity at muscarinic receptor
|
None
|
0.4571
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3D-QSAR study of 8-azabicyclo[3.2.1] octane analogs antagonists of cholinergic receptor.
Year : 2009
Volume : 19
Issue : 11
First Page : 3108
Last Page : 3112
Authors : Verma SM, Razdan BK, Sasmal D.
Abstract : 3D-QSAR models of Comparative of Molecular Field Analysis (CoMFA) and Comparative of Molecular Similarities Indices Analysis (CoMSIA) of 20 8-azabicyclo[3.2.1] octane (potent muscarinic receptor blocker) was performed. These benztropine analogs were optimized using ligand based alignment method. The conventional ligand-based 3D-QSAR studies were performed based on the low energy conformations employing database alignment rule. The ligand-based model gave q(2) value 0.819 and 0.810 and r(2) value 0.991 and 0.988 for CoMFA and CoMSIA, respectively, and the predictive ability of the model was validated. Results indicate that the CoMFA and CoMSIA models could be reliable model which may be used in the design of novel muscarinic antagonists as leads.
|
Inhibition of [3H]NMS binding to muscarinic receptor in mouse N4TG1 neuroblastoma cells
|
Mus musculus
|
3.981
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 3D-QSAR studies of 2,2-diphenylpropionates to aid discovery of novel potent muscarinic antagonists.
Year : 2009
Volume : 17
Issue : 11
First Page : 3999
Last Page : 4012
Authors : Bhattacharjee AK, Gordon JA, Marek E, Campbell A, Gordon RK.
Abstract : Muscarinic acetylcholine receptors (mAChRs) consisting of five known subtypes, are widely distributed in both central and peripheral nervous systems for regulation of a variety of critical functions. The present theoretical study describes correlations between experimental and calculated molecular properties of 15 alpha-substituted 2,2-diphenylpropionate antimuscarinics using quantum chemical and pharmacophore generation methods to characterize the drug mAChR properties and design new therapeutics. The calculated stereoelectronic properties, such as total energies, bond distances, valence angles, torsion angles, HOMO-LUMO energies, reactivity indices, vibrational frequencies of ether and carbonyl moieties, and nitrogen atom proton affinity were found to be well correlated when compared with experimentally determined inhibition constants from the literature using three muscarinic receptor assays: [(3)H]NMS receptor binding, alpha-amylase release from rat pancreas, and guinea pig ileum contraction. In silico predicted toxicity on rat oral LD(50) values correlated well with the [(3)H]NMS binding in N4TG1 cells and alpha-amylase release assays, but not the ileum contraction assay. Next, to explore the functional requirements for potent activity of the compounds, we developed a preliminary 3D pharmacophore model using the in silico techniques. The resulting model contained a hydrogen bond acceptor site on the carbonyl oxygen atom and a ring aromatic feature on one of the two aromatic rings in these compounds. This model was used as a template to search an in-house database for novel analogs. We found compounds equal in inhibition potency to atropine and, importantly, six not reported before as antimuscarinics. These results demonstrate that this QSAR approach not only provides a basis for understanding the molecular mechanism of action but a pharmacophore to aid in the discovery and design of novel potent muscarinic antagonists.
|
Displacement of [3H]NMS from rat recombinant muscarinic M4 receptor expressed in CHO cells after 2 hrs by microplate scintillation counting
|
Rattus norvegicus
|
0.52
nM
|
|
Displacement of [3H]NMS from rat recombinant muscarinic M4 receptor expressed in CHO cells after 2 hrs by microplate scintillation counting
|
Rattus norvegicus
|
0.52
nM
|
|
Journal : Nat. Chem. Biol.
Title : An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission.
Year : 2008
Volume : 4
Issue : 1
First Page : 42
Last Page : 50
Authors : Shirey JK, Xiang Z, Orton D, Brady AE, Johnson KA, Williams R, Ayala JE, Rodriguez AL, Wess J, Weaver D, Niswender CM, Conn PJ.
Abstract : Muscarinic acetylcholine receptors (mAChRs) provide viable targets for the treatment of multiple central nervous system disorders. We have used cheminformatics and medicinal chemistry to develop new, highly selective M4 allosteric potentiators. VU10010, the lead compound, potentiates the M4 response to acetylcholine 47-fold while having no activity at other mAChR subtypes. This compound binds to an allosteric site on the receptor and increases affinity for acetylcholine and coupling to G proteins. Whole-cell patch clamp recordings revealed that selective potentiation of M4 with VU10010 increases carbachol-induced depression of transmission at excitatory but not inhibitory synapses in the hippocampus. The effect was not mimicked by an inactive analog of VU10010 and was absent in M4 knockout mice. Selective regulation of excitatory transmission by M4 suggests that targeting of individual mAChR subtypes could be used to differentially regulate specific aspects of mAChR modulation of function in this important forebrain structure.
|
Displacement of [3H]NMS from rat recombinant muscarinic M1 receptor expressed in CHO cells after 2 hrs by microplate scintillation counting
|
Rattus norvegicus
|
0.79
nM
|
|
Journal : Nat. Chem. Biol.
Title : An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission.
Year : 2008
Volume : 4
Issue : 1
First Page : 42
Last Page : 50
Authors : Shirey JK, Xiang Z, Orton D, Brady AE, Johnson KA, Williams R, Ayala JE, Rodriguez AL, Wess J, Weaver D, Niswender CM, Conn PJ.
Abstract : Muscarinic acetylcholine receptors (mAChRs) provide viable targets for the treatment of multiple central nervous system disorders. We have used cheminformatics and medicinal chemistry to develop new, highly selective M4 allosteric potentiators. VU10010, the lead compound, potentiates the M4 response to acetylcholine 47-fold while having no activity at other mAChR subtypes. This compound binds to an allosteric site on the receptor and increases affinity for acetylcholine and coupling to G proteins. Whole-cell patch clamp recordings revealed that selective potentiation of M4 with VU10010 increases carbachol-induced depression of transmission at excitatory but not inhibitory synapses in the hippocampus. The effect was not mimicked by an inactive analog of VU10010 and was absent in M4 knockout mice. Selective regulation of excitatory transmission by M4 suggests that targeting of individual mAChR subtypes could be used to differentially regulate specific aspects of mAChR modulation of function in this important forebrain structure.
|
Displacement of [3H]NMS from rat recombinant muscarinic M2 receptor expressed in CHO cells after 2 hrs by microplate scintillation counting
|
Rattus norvegicus
|
1.45
nM
|
|
Journal : Nat. Chem. Biol.
Title : An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission.
Year : 2008
Volume : 4
Issue : 1
First Page : 42
Last Page : 50
Authors : Shirey JK, Xiang Z, Orton D, Brady AE, Johnson KA, Williams R, Ayala JE, Rodriguez AL, Wess J, Weaver D, Niswender CM, Conn PJ.
Abstract : Muscarinic acetylcholine receptors (mAChRs) provide viable targets for the treatment of multiple central nervous system disorders. We have used cheminformatics and medicinal chemistry to develop new, highly selective M4 allosteric potentiators. VU10010, the lead compound, potentiates the M4 response to acetylcholine 47-fold while having no activity at other mAChR subtypes. This compound binds to an allosteric site on the receptor and increases affinity for acetylcholine and coupling to G proteins. Whole-cell patch clamp recordings revealed that selective potentiation of M4 with VU10010 increases carbachol-induced depression of transmission at excitatory but not inhibitory synapses in the hippocampus. The effect was not mimicked by an inactive analog of VU10010 and was absent in M4 knockout mice. Selective regulation of excitatory transmission by M4 suggests that targeting of individual mAChR subtypes could be used to differentially regulate specific aspects of mAChR modulation of function in this important forebrain structure.
|
Displacement of [3H]NMS from rat recombinant muscarinic M3 receptor expressed in CHO cells after 2 hrs by microplate scintillation counting
|
Rattus norvegicus
|
0.8
nM
|
|
Journal : Nat. Chem. Biol.
Title : An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission.
Year : 2008
Volume : 4
Issue : 1
First Page : 42
Last Page : 50
Authors : Shirey JK, Xiang Z, Orton D, Brady AE, Johnson KA, Williams R, Ayala JE, Rodriguez AL, Wess J, Weaver D, Niswender CM, Conn PJ.
Abstract : Muscarinic acetylcholine receptors (mAChRs) provide viable targets for the treatment of multiple central nervous system disorders. We have used cheminformatics and medicinal chemistry to develop new, highly selective M4 allosteric potentiators. VU10010, the lead compound, potentiates the M4 response to acetylcholine 47-fold while having no activity at other mAChR subtypes. This compound binds to an allosteric site on the receptor and increases affinity for acetylcholine and coupling to G proteins. Whole-cell patch clamp recordings revealed that selective potentiation of M4 with VU10010 increases carbachol-induced depression of transmission at excitatory but not inhibitory synapses in the hippocampus. The effect was not mimicked by an inactive analog of VU10010 and was absent in M4 knockout mice. Selective regulation of excitatory transmission by M4 suggests that targeting of individual mAChR subtypes could be used to differentially regulate specific aspects of mAChR modulation of function in this important forebrain structure.
|
Displacement of [3H]NMS from rat recombinant muscarinic M5 receptor expressed in CHO cells after 2 hrs by microplate scintillation counting
|
Rattus norvegicus
|
0.86
nM
|
|
Journal : Nat. Chem. Biol.
Title : An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission.
Year : 2008
Volume : 4
Issue : 1
First Page : 42
Last Page : 50
Authors : Shirey JK, Xiang Z, Orton D, Brady AE, Johnson KA, Williams R, Ayala JE, Rodriguez AL, Wess J, Weaver D, Niswender CM, Conn PJ.
Abstract : Muscarinic acetylcholine receptors (mAChRs) provide viable targets for the treatment of multiple central nervous system disorders. We have used cheminformatics and medicinal chemistry to develop new, highly selective M4 allosteric potentiators. VU10010, the lead compound, potentiates the M4 response to acetylcholine 47-fold while having no activity at other mAChR subtypes. This compound binds to an allosteric site on the receptor and increases affinity for acetylcholine and coupling to G proteins. Whole-cell patch clamp recordings revealed that selective potentiation of M4 with VU10010 increases carbachol-induced depression of transmission at excitatory but not inhibitory synapses in the hippocampus. The effect was not mimicked by an inactive analog of VU10010 and was absent in M4 knockout mice. Selective regulation of excitatory transmission by M4 suggests that targeting of individual mAChR subtypes could be used to differentially regulate specific aspects of mAChR modulation of function in this important forebrain structure.
|
Displacement of [3H]-AFDX-384 from human muscarinic M2 receptor expressed in CHO-K1 cells
|
Homo sapiens
|
1.9
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
Year : 2010
Volume : 53
Issue : 17
First Page : 6386
Last Page : 6397
Authors : Sams AG, Hentzer M, Mikkelsen GK, Larsen K, Bundgaard C, Plath N, Christoffersen CT, Bang-Andersen B.
Abstract : The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.
|
Displacement of [3H]-4-DAMP from human muscarinic M3 receptor expressed in BHK-21 cells
|
Homo sapiens
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
Year : 2010
Volume : 53
Issue : 17
First Page : 6386
Last Page : 6397
Authors : Sams AG, Hentzer M, Mikkelsen GK, Larsen K, Bundgaard C, Plath N, Christoffersen CT, Bang-Andersen B.
Abstract : The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.
|
Displacement of [3H]-4-DAMP from human muscarinic M4 receptor expressed in BHK-21 cells
|
Homo sapiens
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
Year : 2010
Volume : 53
Issue : 17
First Page : 6386
Last Page : 6397
Authors : Sams AG, Hentzer M, Mikkelsen GK, Larsen K, Bundgaard C, Plath N, Christoffersen CT, Bang-Andersen B.
Abstract : The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.
|
Displacement of [3H]-4-DAMP from human muscarinic M5 receptor expressed in BHK-21 cells
|
Homo sapiens
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
Year : 2010
Volume : 53
Issue : 17
First Page : 6386
Last Page : 6397
Authors : Sams AG, Hentzer M, Mikkelsen GK, Larsen K, Bundgaard C, Plath N, Christoffersen CT, Bang-Andersen B.
Abstract : The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.
|
Inhibition of rat muscarinic M receptor
|
Rattus norvegicus
|
0.48
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 muscarinic acetylcholine M5 receptor after 1.5 hrs by scintillation counting
|
None
|
0.4
nM
|
|
Journal : Bioorg. Med. Chem.
Title : CNS and antimalarial activity of synthetic meridianin and psammopemmin analogs.
Year : 2011
Volume : 19
Issue : 19
First Page : 5756
Last Page : 5762
Authors : Lebar MD, Hahn KN, Mutka T, Maignan P, McClintock JB, Amsler CD, van Olphen A, Kyle DE, Baker BJ.
Abstract : The marine invertebrate-derived meridianin A, the originally proposed structure for psammopemmin A, and several related 3-pyrimidylindole analogs were synthesized and subsequently investigated for central nervous system, antimalarial, and cytotoxic activity. A Suzuki coupling of an indoleborate ester to the pyrimidine electrophile was utilized to form the natural product and derivatives thereof. The 3-pyrimidineindoles were found to prevent radioligand binding to several CNS receptors and transporters, most notably, serotonin receptors (<0.2 μM K(i) for 5HT(2B)). Two compounds also inhibited the human malaria parasite Plasmodium falciparum (IC(50) <50 μM). Only the natural product was cytotoxic toward A549 cells (IC(50)=15 μM).
|
DRUGMATRIX: Muscarinic M1 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
1.521
nM
|
|
DRUGMATRIX: Muscarinic M1 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
0.366
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Muscarinic M2 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
3.735
nM
|
|
DRUGMATRIX: Muscarinic M2 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
1.328
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Muscarinic M3 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
2.071
nM
|
|
DRUGMATRIX: Muscarinic M3 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
0.439
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Muscarinic M4 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
0.744
nM
|
|
DRUGMATRIX: Muscarinic M4 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
0.104
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Muscarinic M5 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
0.922
nM
|
|
DRUGMATRIX: Muscarinic M5 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
0.662
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-1D adrenergic receptor radioligand binding (ligand: prazosin)
|
None
|
666.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2C radioligand binding (ligand: [3H] Mesulergine)
|
None
|
530.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Competitive inhibition of EGFP-fused human M1 receptor N-terminal truncated at 17 residues expressed in HEK293 cells after 4 hrs by FRET assay in presence of para-LRB-AC42
|
Homo sapiens
|
1.202
nM
|
|
Journal : J. Med. Chem.
Title : Fluorescent derivatives of AC-42 to probe bitopic orthosteric/allosteric binding mechanisms on muscarinic M1 receptors.
Year : 2012
Volume : 55
Issue : 5
First Page : 2125
Last Page : 2143
Authors : Daval SB, Valant C, Bonnet D, Kellenberger E, Hibert M, Galzi JL, Ilien B.
Abstract : Two fluorescent derivatives of the M1 muscarinic selective agonist AC-42 were synthesized by coupling the lissamine rhodamine B fluorophore (in ortho and para positions) to AC42-NH(2). This precursor, prepared according to an original seven-step procedure, was included in the study together with the LRB fluorophore (alone or linked to an alkyl chain). All these compounds are antagonists, but examination of their ability to inhibit or modulate orthosteric [(3)H]NMS binding revealed that para-LRB-AC42 shared several properties with AC-42. Carefully designed experiments allowed para-LRB-AC42 to be used as a FRET tracer on EGFP-fused M1 receptors. Under equilibrium binding conditions, orthosteric ligands, AC-42, and the allosteric modulator gallamine behaved as competitors of para-LRB-AC42 binding whereas other allosteric compounds such as WIN 51,708 and N-desmethylclozapine were noncompetitive inhibitors. Finally, molecular modeling studies focused on putative orthosteric/allosteric bitopic poses for AC-42 and para-LRB-AC42 in a 3D model of the human M1 receptor.
|
Displacement of [3H]NMS from EGFP-fused human M1 receptor N-terminal truncated at 17 residues expressed in HEK293 cells after 22 hrs by liquid scintillation counting
|
Homo sapiens
|
0.5754
nM
|
|
Journal : J. Med. Chem.
Title : Fluorescent derivatives of AC-42 to probe bitopic orthosteric/allosteric binding mechanisms on muscarinic M1 receptors.
Year : 2012
Volume : 55
Issue : 5
First Page : 2125
Last Page : 2143
Authors : Daval SB, Valant C, Bonnet D, Kellenberger E, Hibert M, Galzi JL, Ilien B.
Abstract : Two fluorescent derivatives of the M1 muscarinic selective agonist AC-42 were synthesized by coupling the lissamine rhodamine B fluorophore (in ortho and para positions) to AC42-NH(2). This precursor, prepared according to an original seven-step procedure, was included in the study together with the LRB fluorophore (alone or linked to an alkyl chain). All these compounds are antagonists, but examination of their ability to inhibit or modulate orthosteric [(3)H]NMS binding revealed that para-LRB-AC42 shared several properties with AC-42. Carefully designed experiments allowed para-LRB-AC42 to be used as a FRET tracer on EGFP-fused M1 receptors. Under equilibrium binding conditions, orthosteric ligands, AC-42, and the allosteric modulator gallamine behaved as competitors of para-LRB-AC42 binding whereas other allosteric compounds such as WIN 51,708 and N-desmethylclozapine were noncompetitive inhibitors. Finally, molecular modeling studies focused on putative orthosteric/allosteric bitopic poses for AC-42 and para-LRB-AC42 in a 3D model of the human M1 receptor.
|
Antiamoebic activity against Entamoeba histolytica
|
Entamoeba histolytica
|
100.0
ug.mL-1
|
|
Journal : Med Chem Res
Title : Exploring QSAR of antiamoebic agents of isolated natural products by MLR, ANN, and RTO
Year : 2012
Volume : 21
Issue : 9
First Page : 2501
Last Page : 2516
Authors : Ramirez-Galicia G, Martinez-Pacheco H, Garduno-Juarez R, Deeb O
|
Ionotropic activity in Cavia porcellus (guinea pig) ileum assessed as inhibition of acetylcholine-induced contraction after 15 min by physiographic analysis
|
Cavia porcellus
|
3.981
nM
|
|
Journal : Med Chem Res
Title : Synthesis and biological evaluation of N 1,N 2-bis-[4-(t-amino)-2-butynyl]phthalamides as oxotremorine and acetylcholine antagonists
Year : 2013
Volume : 22
Issue : 4
First Page : 1597
Last Page : 1603
Authors : Muhi-eldeen Z, Al-Kaissi E, Ghantous H
|
Displacement of [3H]NMS from rat muscarinic M1 receptor expressed in CHO cells after 3 hrs
|
Rattus norvegicus
|
1.38
nM
|
|
Displacement of [3H]NMS from rat muscarinic M1 receptor expressed in CHO cells after 3 hrs
|
Rattus norvegicus
|
1.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Further exploration of M₁ allosteric agonists: subtle structural changes abolish M₁ allosteric agonism and result in pan-mAChR orthosteric antagonism.
Year : 2013
Volume : 23
Issue : 1
First Page : 223
Last Page : 227
Authors : Sheffler DJ, Sevel C, Le U, Lovell KM, Tarr JC, Carrington SJ, Cho HP, Digby GJ, Niswender CM, Conn PJ, Hopkins CR, Wood MR, Lindsley CW.
Abstract : This letter describes the further exploration of two series of M(1) allosteric agonists, TBPB and VU0357017, previously reported from our lab. Within the TPBP scaffold, either electronic or steric perturbations to the central piperidine ring led to a loss of selective M(1) allosteric agonism and afforded pan-mAChR antagonism, which was demonstrated to be mediated via the orthosteric site. Additional SAR around a related M(1) allosteric agonist family (VU0357017) identified similar, subtle 'molecular switches' that modulated modes of pharmacology from allosteric agonism to pan-mAChR orthosteric antagonism. Therefore, all of these ligands are best classified as bi-topic ligands that possess high affinity binding at an allosteric site to engender selective M(1) activation, but all bind, at higher concentrations, to the orthosteric ACh site, leading to non-selective orthosteric site binding and mAChR antagonism.
|
Displacement of [3H] N-methylscopolamine from human muscarinic M4 receptor expressed in CHOK1 cells after 30 mins by scintillation counting analysis
|
Homo sapiens
|
1.39
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.
|
Displacement of [3H] N-methylscopolamine from human muscarinic M3 receptor expressed in CHOK1 cells after 30 mins by scintillation counting analysis
|
Homo sapiens
|
2.18
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.
|
Displacement of [3H] N-methylscopolamine from human muscarinic M2 receptor expressed in CHOK1 cells after 30 mins by scintillation counting analysis
|
Homo sapiens
|
1.44
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.
|
Displacement of [3H] N-methylscopolamine from human muscarinic M1 receptor expressed in CHOK1 cells after 30 mins by scintillation counting analysis
|
Homo sapiens
|
0.922
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.
|
Displacement of [3H] N-methylscopolamine from muscarinic acetylcholine receptor in guinea pig brain homogenate after 30 mins by scintillation counting analysis
|
Cavia porcellus
|
2.49
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.
|
Inhibition of muscarinic acetylcholine receptor in rat cortex
|
Rattus norvegicus
|
0.12
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.
|
Displacement of [3H]NMS from human muscarinic acetylcholine receptor subtype 5 expressed in CHO cell membranes by scintillation counting method
|
Homo sapiens
|
1.47
nM
|
|
Journal : J. Med. Chem.
Title : Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380).
Year : 2014
Volume : 57
Issue : 18
First Page : 7804
Last Page : 7810
Authors : Gentry PR, Kokubo M, Bridges TM, Noetzel MJ, Cho HP, Lamsal A, Smith E, Chase P, Hodder PS, Niswender CM, Daniels JS, Conn PJ, Lindsley CW, Wood MR.
Abstract : A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M5). Application of rapid analog, iterative parallel synthesis efficiently optimized M5 potency to arrive at the most potent M5 PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M5 EC50 = 190 nM, rat M5 EC50 = 610 nM, brain to plasma ratio (Kp) of 0.36).
|
Displacement of [3H]-quinuclydinyl benzylate from muscarinic receptor (unknown origin)
|
Homo sapiens
|
470.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 4-Fluoro-3',4',5'-trimethoxychalcone as a new anti-invasive agent. From discovery to initial validation in an in vivo metastasis model.
Year : 2015
Volume : 101
First Page : 627
Last Page : 639
Authors : Roman BI, De Ryck T, Patronov A, Slavov SH, Vanhoecke BW, Katritzky AR, Bracke ME, Stevens CV.
Abstract : Invasion and metastasis are responsible for 90% of cancer-related mortality. Herein, we report on our quest for novel, clinically relevant inhibitors of local invasion, based on a broad screen of natural products in a phenotypic assay. Starting from micromolar chalcone hits, a predictive QSAR model for diaryl propenones was developed, and synthetic analogues with a 100-fold increase in potency were obtained. Two nanomolar hits underwent efficacy validation and eADMET profiling; one compound was shown to increase the survival time in an artificial metastasis model in nude mice. Although the molecular mechanism(s) by which these substances mediate efficacy remain(s) unrevealed, we were able to eliminate the major targets commonly associated with antineoplastic chalcones.
|
Displacement of [3H]-NMS from recombinant human M4 receptor expressed in CHO cell membranes
|
Homo sapiens
|
1.6
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype.
Year : 2017
Volume : 27
Issue : 11
First Page : 2479
Last Page : 2483
Authors : Bender AM, Weiner RL, Luscombe VB, Cho HP, Niswender CM, Engers DW, Bridges TM, Conn PJ, Lindsley CW.
Abstract : This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M4 (IC50s<300nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma Kp,uu=0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CLp=5.37mL/min/kg). Surprisingly, this series displayed pan-muscarinic antagonist activity across M1-5, despite the absence of the prototypical basic or quaternary amine moiety, thus offering a new chemotype from which to develop a next generation of pan-muscarinic antagonist agents.
|
Displacement of [3H]UNSW-MK259 from human muscarinic acetylcholine receptor M2 expressed in CHOK9 cells after 3 hrs by liquid scintillation counting assay
|
Homo sapiens
|
0.8128
nM
|
|
Journal : J Med Chem
Title : Radiolabeled Dibenzodiazepinone-Type Antagonists Give Evidence of Dualsteric Binding at the M2 Muscarinic Acetylcholine Receptor.
Year : 2017
Volume : 60
Issue : 8
First Page : 3314
Last Page : 3334
Authors : Pegoli A, She X, Wifling D, Hübner H, Bernhardt G, Gmeiner P, Keller M.
Abstract : The dualsteric ligand approach, aiming at ligands with improved subtype selectivity, has been increasingly applied to muscarinic receptors (MRs). In this article, we present the synthesis and characterization of a M2R subtype-preferring radiolabeled dibenzodiazepinone-type antagonist ([3H]UNSW-MK259, [3H]19) and its homodimeric analogue [3H]UR-AP060 ([3H]33). Saturation binding studies at the M2R, using the orthosteric antagonist atropine to determine unspecific binding, proved that the monomeric and the dimeric compound bind to the orthosteric binding site (apparent Kd: 0.87 and 0.31 nM, respectively). Various binding studies with [3H]19 and [3H]33 at the M2R, for instance, saturation binding experiments in the presence of the allosteric MR modulators W84 (8) or LY2119620 (9) (Schild-like analysis) suggested a competitive mechanism between the allosteric modulator and the dibenzodiazepinone derivatives, and thus a dualsteric binding mode of both 19 and 33. This was consistent with the results of M2R MD simulations (≥2 μs) performed with 19 and 33.
|
Displacement of [3H]UR-AP060 from human muscarinic acetylcholine receptor M2 expressed in CHOK9 cell homogenate after 3 hrs by liquid scintillation counting assay
|
Homo sapiens
|
16.98
nM
|
|
Journal : J Med Chem
Title : Radiolabeled Dibenzodiazepinone-Type Antagonists Give Evidence of Dualsteric Binding at the M2 Muscarinic Acetylcholine Receptor.
Year : 2017
Volume : 60
Issue : 8
First Page : 3314
Last Page : 3334
Authors : Pegoli A, She X, Wifling D, Hübner H, Bernhardt G, Gmeiner P, Keller M.
Abstract : The dualsteric ligand approach, aiming at ligands with improved subtype selectivity, has been increasingly applied to muscarinic receptors (MRs). In this article, we present the synthesis and characterization of a M2R subtype-preferring radiolabeled dibenzodiazepinone-type antagonist ([3H]UNSW-MK259, [3H]19) and its homodimeric analogue [3H]UR-AP060 ([3H]33). Saturation binding studies at the M2R, using the orthosteric antagonist atropine to determine unspecific binding, proved that the monomeric and the dimeric compound bind to the orthosteric binding site (apparent Kd: 0.87 and 0.31 nM, respectively). Various binding studies with [3H]19 and [3H]33 at the M2R, for instance, saturation binding experiments in the presence of the allosteric MR modulators W84 (8) or LY2119620 (9) (Schild-like analysis) suggested a competitive mechanism between the allosteric modulator and the dibenzodiazepinone derivatives, and thus a dualsteric binding mode of both 19 and 33. This was consistent with the results of M2R MD simulations (≥2 μs) performed with 19 and 33.
|
Displacement of [3H]NMS from human muscarinic acetylcholine receptor M2 expressed in CHOK1 cells
|
Homo sapiens
|
15.85
nM
|
|
Journal : J Med Chem
Title : Radiolabeled Dibenzodiazepinone-Type Antagonists Give Evidence of Dualsteric Binding at the M2 Muscarinic Acetylcholine Receptor.
Year : 2017
Volume : 60
Issue : 8
First Page : 3314
Last Page : 3334
Authors : Pegoli A, She X, Wifling D, Hübner H, Bernhardt G, Gmeiner P, Keller M.
Abstract : The dualsteric ligand approach, aiming at ligands with improved subtype selectivity, has been increasingly applied to muscarinic receptors (MRs). In this article, we present the synthesis and characterization of a M2R subtype-preferring radiolabeled dibenzodiazepinone-type antagonist ([3H]UNSW-MK259, [3H]19) and its homodimeric analogue [3H]UR-AP060 ([3H]33). Saturation binding studies at the M2R, using the orthosteric antagonist atropine to determine unspecific binding, proved that the monomeric and the dimeric compound bind to the orthosteric binding site (apparent Kd: 0.87 and 0.31 nM, respectively). Various binding studies with [3H]19 and [3H]33 at the M2R, for instance, saturation binding experiments in the presence of the allosteric MR modulators W84 (8) or LY2119620 (9) (Schild-like analysis) suggested a competitive mechanism between the allosteric modulator and the dibenzodiazepinone derivatives, and thus a dualsteric binding mode of both 19 and 33. This was consistent with the results of M2R MD simulations (≥2 μs) performed with 19 and 33.
|
Displacement of [3H]NMS from human recombinant muscarinic M4 receptor expressed in CHO cell membranes
|
Homo sapiens
|
0.64
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists.
Year : 2017
Volume : 27
Issue : 15
First Page : 3576
Last Page : 3581
Authors : Bender AM, Weiner RL, Luscombe VB, Ajmera S, Cho HP, Chang S, Zhan X, Rodriguez AL, Niswender CM, Engers DW, Bridges TM, Conn PJ, Lindsley CW.
Abstract : This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M4 (hM4 IC50s<200nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma Kp=2.1, Kp,uu=1.1). Despite the absence of the prototypical mAChR antagonist basic or quaternary amine moiety, this series displayed pan-muscarinic antagonist activity across M1-5 (with 9- to 16-fold functional selectivity at best). This series further expands the chemical diversity of mAChR antagonists.
|
Antagonist potency at muscarinic M3 receptor in guinea-pig ileum assessed as inhibition of carbachol-induced contractions after 15 mins
|
Cavia porcellus
|
1.023
nM
|
|
Journal : Bioorg Med Chem
Title : Novel naphthyloxy derivatives - Potent histamine H3 receptor ligands. Synthesis and pharmacological evaluation.
Year : 2018
Volume : 26
Issue : 9
First Page : 2573
Last Page : 2585
Authors : Łażewska D, Kaleta M, Hagenow S, Mogilski S, Latacz G, Karcz T, Lubelska A, Honkisz E, Handzlik J, Reiner D, Satała G, Filipek B, Stark H, Kieć-Kononowicz K.
Abstract : A series of 1- and 2-naphthyloxy derivatives were synthesized and evaluated for histamine H3 receptor affinity. Most compounds showed high affinities with Ki values below 100 nM. The most potent ligand, 1-(5-(naphthalen-1-yloxy)pentyl)azepane (11) displayed high affinity for the histamine H3 receptor with a Ki value of 21.9 nM. The antagonist behaviour of 11 was confirmed both in vitro in the cAMP assay (IC50 = 312 nM) and in vivo in the rat dipsogenia model (ED50 = 3.68 nM). Moreover, compound 11 showed positive effects on scopolamine induced-memory deficits in mice (at doses of 10 and 15 mg/kg) and an analgesic effect in the formalin test in mice with ED50 = 30.6 mg/kg (early phase) and ED50 = 20.8 mg/kg (late phase). Another interesting compound, 1-(5-(Naphthalen-1-yloxy)pentyl)piperidine (13; H3R Ki = 53.9 nM), was accepted for Anticonvulsant Screening Program at the National Institute of Neurological Disorders and Stroke/National Institute of Health (Rockville, USA). The screening was performed in the maximal electroshock seizure (MES), the subcutaneous pentylenetetrazole (scPTZ) and the 6-Hz psychomotor animal models of epilepsy. Neurologic deficit was evaluated by the rotarod test. Compound 13 inhibited convulsions induced by the MES with ED50 of 19.2 mg/kg (mice, i.p.), 17.8 (rats, i.p.), and 78.1 (rats, p.o.). Moreover, 13 displayed protection against the 6-Hz psychomotor seizures (32 mA) in mice (i.p.) with ED50 of 33.1 mg/kg and (44 mA) ED50 of 57.2 mg/kg. Furthermore, compounds 11 and 13 showed in vitro weak influence on viability of tested cell lines (normal HEK293, neuroblastoma IMR-32, hepatoma HEPG2), weak inhibition of CYP3A4 activity, and no mutagenicity. Thus, these compounds may be used as leads in a further search for histamine H3 receptor ligands with promising in vitro and in vivo activity.
|
Antagonist activity at muscarinic receptor in guinea pig ileum assessed as carbachol-induced ileum contraction measured after 15 mins
|
Cavia porcellus
|
1.035
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological activity of novel tert-butyl and tert-pentylphenoxyalkyl piperazine derivatives as histamine H3R ligands.
Year : 2018
Volume : 152
First Page : 223
Last Page : 234
Authors : Szczepańska K, Karcz T, Mogilski S, Siwek A, Kuder KJ, Latacz G, Kubacka M, Hagenow S, Lubelska A, Olejarz A, Kotańska M, Sadek B, Stark H, Kieć-Kononowicz K.
Abstract : As a continuation of our search for novel histamine H3 receptor ligands, a series of twenty four new tert-butyl and tert-pentyl phenoxyalkylamine derivatives (2-25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer were evaluated for their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for 4-pyridyl derivatives 4, 10, 16 and 22 (Ki = 16.0-120 nM). As it has been shown in docking studies, those specific heteroaromatic 4-N piperazine substituents might interact with one of the key receptor interacting amino acids. Moreover, the most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure (MES) model in mice. Furthermore, the blood-brain barrier penetration, the functional H3R antagonist potency as well as the pro-cognitive properties in the passive avoidance test were demonstrated for compound 10. In order to estimate drug-likeness of compound 10,in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. In addition, paying attention to the results obtained within this study, the 4-pyridyl-piperazino moiety has been established as a new bioisosteric piperidine replacement in H3R ligands.
|
Displacement of [3H]NMS from human M1 AChR expressed in CHO cell membranes after 1 to 2 hrs by liquid scintillation spectrometry method
|
Homo sapiens
|
0.44
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Muscarinic agonist, (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate: High affinity, but low subtype selectivity for human M1 - M5 muscarinic acetylcholine receptors.
Year : 2019
Volume : 29
Issue : 3
First Page : 471
Last Page : 476
Authors : Lee NR, Gujarathi S, Bommagani S, Siripurapu K, Zheng G, Dwoskin LP.
Abstract : Novel quinuclidinyl N-phenylcarbamate analogs were synthesized, and binding affinities at M1-M5 muscarinic acetylcholine receptor (mAChR) subtypes were determined using Chinese hamster ovary (CHO) cell membranes stably expressing one specific subtype of human mAChR. Although not subtype selective, the lead analog (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate (3c) exhibited the highest affinity (Ki = 2.0, 13, 2.6, 2.2, 1.8 nM) at each of the M1-M5 mAChRs, respectively. Based on results from the [3H]dopamine release assay using rat striatal slices, 3c acted as an agonist at mAChRs. The effect of 3c was inhibited by the nonselective mAChR antagonist, scopolamine, and 3c augmented release evoked by oxotremorine. A potent analog from the same scaffold, (±)-quinuclidin-3-yl-(4-methoxyphenethyl)(phenyl)-carbamate (3b) exhibited the greatest selectivity (17-fold) at M3 over M2 mAChRs. These analogs could serve as leads for further discovery of novel subtype-selective muscarinic ligands with the goal of providing therapeutics for substance use disorders and chronic obstructive pulmonary disease.
|
Displacement of [3H]NMS from human M2 AChR expressed in CHO cell membranes after 1 to 2 hrs by liquid scintillation spectrometry method
|
Homo sapiens
|
0.9
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Muscarinic agonist, (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate: High affinity, but low subtype selectivity for human M1 - M5 muscarinic acetylcholine receptors.
Year : 2019
Volume : 29
Issue : 3
First Page : 471
Last Page : 476
Authors : Lee NR, Gujarathi S, Bommagani S, Siripurapu K, Zheng G, Dwoskin LP.
Abstract : Novel quinuclidinyl N-phenylcarbamate analogs were synthesized, and binding affinities at M1-M5 muscarinic acetylcholine receptor (mAChR) subtypes were determined using Chinese hamster ovary (CHO) cell membranes stably expressing one specific subtype of human mAChR. Although not subtype selective, the lead analog (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate (3c) exhibited the highest affinity (Ki = 2.0, 13, 2.6, 2.2, 1.8 nM) at each of the M1-M5 mAChRs, respectively. Based on results from the [3H]dopamine release assay using rat striatal slices, 3c acted as an agonist at mAChRs. The effect of 3c was inhibited by the nonselective mAChR antagonist, scopolamine, and 3c augmented release evoked by oxotremorine. A potent analog from the same scaffold, (±)-quinuclidin-3-yl-(4-methoxyphenethyl)(phenyl)-carbamate (3b) exhibited the greatest selectivity (17-fold) at M3 over M2 mAChRs. These analogs could serve as leads for further discovery of novel subtype-selective muscarinic ligands with the goal of providing therapeutics for substance use disorders and chronic obstructive pulmonary disease.
|
Displacement of [3H]NMS from human M3 AChR expressed in CHO cell membranes after 1 to 2 hrs by liquid scintillation spectrometry method
|
Homo sapiens
|
0.53
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Muscarinic agonist, (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate: High affinity, but low subtype selectivity for human M1 - M5 muscarinic acetylcholine receptors.
Year : 2019
Volume : 29
Issue : 3
First Page : 471
Last Page : 476
Authors : Lee NR, Gujarathi S, Bommagani S, Siripurapu K, Zheng G, Dwoskin LP.
Abstract : Novel quinuclidinyl N-phenylcarbamate analogs were synthesized, and binding affinities at M1-M5 muscarinic acetylcholine receptor (mAChR) subtypes were determined using Chinese hamster ovary (CHO) cell membranes stably expressing one specific subtype of human mAChR. Although not subtype selective, the lead analog (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate (3c) exhibited the highest affinity (Ki = 2.0, 13, 2.6, 2.2, 1.8 nM) at each of the M1-M5 mAChRs, respectively. Based on results from the [3H]dopamine release assay using rat striatal slices, 3c acted as an agonist at mAChRs. The effect of 3c was inhibited by the nonselective mAChR antagonist, scopolamine, and 3c augmented release evoked by oxotremorine. A potent analog from the same scaffold, (±)-quinuclidin-3-yl-(4-methoxyphenethyl)(phenyl)-carbamate (3b) exhibited the greatest selectivity (17-fold) at M3 over M2 mAChRs. These analogs could serve as leads for further discovery of novel subtype-selective muscarinic ligands with the goal of providing therapeutics for substance use disorders and chronic obstructive pulmonary disease.
|
Displacement of [3H]NMS from human M5 AChR expressed in CHO cell membranes after 1 to 2 hrs by liquid scintillation spectrometry method
|
Homo sapiens
|
0.6
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Muscarinic agonist, (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate: High affinity, but low subtype selectivity for human M1 - M5 muscarinic acetylcholine receptors.
Year : 2019
Volume : 29
Issue : 3
First Page : 471
Last Page : 476
Authors : Lee NR, Gujarathi S, Bommagani S, Siripurapu K, Zheng G, Dwoskin LP.
Abstract : Novel quinuclidinyl N-phenylcarbamate analogs were synthesized, and binding affinities at M1-M5 muscarinic acetylcholine receptor (mAChR) subtypes were determined using Chinese hamster ovary (CHO) cell membranes stably expressing one specific subtype of human mAChR. Although not subtype selective, the lead analog (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate (3c) exhibited the highest affinity (Ki = 2.0, 13, 2.6, 2.2, 1.8 nM) at each of the M1-M5 mAChRs, respectively. Based on results from the [3H]dopamine release assay using rat striatal slices, 3c acted as an agonist at mAChRs. The effect of 3c was inhibited by the nonselective mAChR antagonist, scopolamine, and 3c augmented release evoked by oxotremorine. A potent analog from the same scaffold, (±)-quinuclidin-3-yl-(4-methoxyphenethyl)(phenyl)-carbamate (3b) exhibited the greatest selectivity (17-fold) at M3 over M2 mAChRs. These analogs could serve as leads for further discovery of novel subtype-selective muscarinic ligands with the goal of providing therapeutics for substance use disorders and chronic obstructive pulmonary disease.
|
Antagonist activity at human muscarinic M2 receptor expressed in HEK293 cells co-expressing HA-Galphaq/i5 assessed as inhibition of carbachol-induced IP1 accumulation pre-incubated for 30 mins followed by carbachol addition and measured after 1 hr by HTRF assay
|
Homo sapiens
|
8.128
nM
|
|
Journal : J Med Chem
Title : Conjugation of Short Peptides to Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Determines M<sub>2</sub>R Selectivity.
Year : 2019
Volume : 62
Issue : 11
First Page : 5358
Last Page : 5369
Authors : Pegoli A, Wifling D, Gruber CG, She X, Hübner H, Bernhardt G, Gmeiner P, Keller M.
Abstract : Muscarinic acetylcholine receptors (MRs), comprising five subtypes (M<sub>1</sub>R-M<sub>5</sub>R) in humans, exhibit a high degree of structural similarity. Therefore, subtype-selective MR agonists and antagonists are lacking. We present an approach to highly M<sub>2</sub>R-selective MR antagonists based on the conjugation of di- or tripeptides to M<sub>2</sub>R-preferring dibenzodiazepinone-type MR antagonists. M<sub>2</sub>R selectivity was dependent on the peptide sequence and on the type of linker. The introduction of basic amino acids resulted in improved M<sub>2</sub>R selectivity (e.g., UR-AP148 (48): p K<sub>i</sub> (hM<sub>2</sub>R) of 8.97, ratio of K<sub>i</sub> M<sub>1</sub>R/M<sub>2</sub>R/M<sub>3</sub>R/M<sub>4</sub>R/M<sub>5</sub>R of 49:1:6500:60:400) compared to reported pyridobenzo- and dibenzodiazepinone-type MR ligands. A supposed dualsteric binding mode of the DIBA-peptide conjugates, such as 48, at MRs was supported by molecular dynamics simulations.
|
Antagonist activity at muscarinic M3 receptor in guinea-pig ileum assessed as inhibition of carbachol-induced contractions after 15 mins
|
Cavia porcellus
|
1.023
nM
|
|
Journal : Bioorg Med Chem
Title : Alkyl derivatives of 1,3,5-triazine as histamine H<sub>4</sub> receptor ligands.
Year : 2019
Volume : 27
Issue : 7
First Page : 1254
Last Page : 1262
Authors : Łażewska D, Mogilski S, Hagenow S, Kuder K, Głuch-Lutwin M, Siwek A, Więcek M, Kaleta M, Seibel U, Buschauer A, Filipek B, Stark H, Kieć-Kononowicz K.
Abstract : This study focuses on the design, synthesis, molecular modeling and biological evaluation of a novel group of alkyl-1,3,5-triazinyl-methylpiperazines. New compounds were synthesized and their affinities for human histamine H<sub>4</sub> receptor (hH<sub>4</sub>R) were evaluated. Among them, 4-(cyclohexylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (14) exhibited hH<sub>4</sub>R affinity with a K<sub>i</sub> of 160 nM and behaved as antagonist in functional assays: the cellular aequorin-based assay (IC<sub>50</sub> = 32 nM) and [<sup>35</sup>S]GTPγS binding assay (pK<sub>b</sub> = 6.67). In addition, antinociceptive activity of 14in vivo was observed in Formalin test (in mice) and in Carrageenan-induced acute inflammation test (in rats).
|
Antagonist activity at human muscarinic M2 receptor expressed in HEK293 cells co-expressing HA-Galphaq/i5 assessed as inhibition of carbachol-induced IP1 accumulation at 37 degree C pre-incubated for 30 mins followed by carbachol addition and measured after 60 mins by HTRF assay
|
Homo sapiens
|
8.128
nM
|
|
Journal : J Med Chem
Title : Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M<sub>2</sub> Receptor.
Year : 2020
Volume : 63
Issue : 8
First Page : 4133
Last Page : 4154
Authors : She X, Pegoli A, Gruber CG, Wifling D, Carpenter J, Hübner H, Chen M, Wan J, Bernhardt G, Gmeiner P, Holliday ND, Keller M.
Abstract : Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M<sub>2</sub>R affinities (p<i>K</i><sub>i</sub> (radioligand competition binding): 9.10-9.59). Binding studies at M<sub>1</sub> and M<sub>3</sub>-M<sub>5</sub> receptors indicated a M<sub>2</sub>R preference. Flow cytometric and high-content imaging saturation and competition binding (M<sub>1</sub>R, M<sub>2</sub>R, and M<sub>4</sub>R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM<sub>2</sub>R cells). Results from dissociation and saturation binding experiments (M<sub>2</sub>R) in the presence of allosteric M<sub>2</sub>R modulators (dissociation: W84, LY2119620, and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M<sub>2</sub>R in imaging and binding studies and suggest that they have a dualsteric mode of action.
|
Displacement of 4-(2-((1E,3E)-5-((E)-3,3-Dimethyl-1-(6-oxo-6-((2-(4-(4-(1-(2-oxo-2-(11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)ethyl)piperidin-4-yl)butyl)piperazin-1-yl)ethyl)amino)hexyl)-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-3,3-dimethyl-3H-indol-1-ium-1-yl)butane-1-sulfonate Bis(hydrotrifluoroacetate) fluorescent tracer from human muscarinic M2 receptor expressed in CHO-K9 cells by FACSCalibur flow cytometry
|
Homo sapiens
|
2.512
nM
|
|
Journal : J Med Chem
Title : Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M<sub>2</sub> Receptor.
Year : 2020
Volume : 63
Issue : 8
First Page : 4133
Last Page : 4154
Authors : She X, Pegoli A, Gruber CG, Wifling D, Carpenter J, Hübner H, Chen M, Wan J, Bernhardt G, Gmeiner P, Holliday ND, Keller M.
Abstract : Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M<sub>2</sub>R affinities (p<i>K</i><sub>i</sub> (radioligand competition binding): 9.10-9.59). Binding studies at M<sub>1</sub> and M<sub>3</sub>-M<sub>5</sub> receptors indicated a M<sub>2</sub>R preference. Flow cytometric and high-content imaging saturation and competition binding (M<sub>1</sub>R, M<sub>2</sub>R, and M<sub>4</sub>R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM<sub>2</sub>R cells). Results from dissociation and saturation binding experiments (M<sub>2</sub>R) in the presence of allosteric M<sub>2</sub>R modulators (dissociation: W84, LY2119620, and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M<sub>2</sub>R in imaging and binding studies and suggest that they have a dualsteric mode of action.
|
Displacement of 4-(2-((1E,3E)-5-((E)-3,3-Dimethyl-1-(6-oxo-6-((2-(4-(4-(1-(2-oxo-2-(11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)ethyl)piperidin-4-yl)butyl)piperazin-1-yl)ethyl)amino)hexyl)indolin-2-ylidene)penta-1,3-dien-1-yl)-3,3-dimethyl-3H-indol-1-ium-1-yl)butane-1-sulfonate Tris(hydrotrifluoroacetate fluorescent tracer from human muscarinic M2 receptor expressed in CHO-K9 cells measured after 60 mins by Hoechst H33342 dye based confocal plate reader assay
|
Homo sapiens
|
18.62
nM
|
|
Journal : J Med Chem
Title : Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M<sub>2</sub> Receptor.
Year : 2020
Volume : 63
Issue : 8
First Page : 4133
Last Page : 4154
Authors : She X, Pegoli A, Gruber CG, Wifling D, Carpenter J, Hübner H, Chen M, Wan J, Bernhardt G, Gmeiner P, Holliday ND, Keller M.
Abstract : Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M<sub>2</sub>R affinities (p<i>K</i><sub>i</sub> (radioligand competition binding): 9.10-9.59). Binding studies at M<sub>1</sub> and M<sub>3</sub>-M<sub>5</sub> receptors indicated a M<sub>2</sub>R preference. Flow cytometric and high-content imaging saturation and competition binding (M<sub>1</sub>R, M<sub>2</sub>R, and M<sub>4</sub>R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM<sub>2</sub>R cells). Results from dissociation and saturation binding experiments (M<sub>2</sub>R) in the presence of allosteric M<sub>2</sub>R modulators (dissociation: W84, LY2119620, and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M<sub>2</sub>R in imaging and binding studies and suggest that they have a dualsteric mode of action.
|
Displacement of 4-(2-((1E,3E)-5-((E)-3,3-Dimethyl-1-(6-oxo-6-((2-(4-(4-(1-(2-oxo-2-(11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)ethyl)piperidin-4-yl)butyl)piperazin-1-yl)ethyl)amino)hexyl)-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-3,3-dimethyl-3H-indol-1-ium-1-yl)butane-1-sulfonate Bis(hydrotrifluoroacetate) fluorescent tracer from human muscarinic M2 receptor expressed in CHO-K9 cells measured after 60 mins by Hoechst H33342 dye based confocal plate reader assay
|
Homo sapiens
|
4.898
nM
|
|
Journal : J Med Chem
Title : Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M<sub>2</sub> Receptor.
Year : 2020
Volume : 63
Issue : 8
First Page : 4133
Last Page : 4154
Authors : She X, Pegoli A, Gruber CG, Wifling D, Carpenter J, Hübner H, Chen M, Wan J, Bernhardt G, Gmeiner P, Holliday ND, Keller M.
Abstract : Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M<sub>2</sub>R affinities (p<i>K</i><sub>i</sub> (radioligand competition binding): 9.10-9.59). Binding studies at M<sub>1</sub> and M<sub>3</sub>-M<sub>5</sub> receptors indicated a M<sub>2</sub>R preference. Flow cytometric and high-content imaging saturation and competition binding (M<sub>1</sub>R, M<sub>2</sub>R, and M<sub>4</sub>R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM<sub>2</sub>R cells). Results from dissociation and saturation binding experiments (M<sub>2</sub>R) in the presence of allosteric M<sub>2</sub>R modulators (dissociation: W84, LY2119620, and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M<sub>2</sub>R in imaging and binding studies and suggest that they have a dualsteric mode of action.
|
Displacement of 4-(2-((1E,3E)-5-((E)-3,3-Dimethyl-1-(6-oxo-6-((2-(3-(1-(4-(1-(2-oxo-2-(11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)ethyl)piperidin-4-yl)butyl)-1H-imidazol-4-yl)propanamido)ethyl)-amino)hexyl)-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-3,3-dimethyl-3H-indol-1-ium-1-yl)butane-1-sulfonateHydrotrifluoroacetate fluorescent tracer from human muscarinic M2 receptor expressed in CHO-K9 cells measured after 60 mins by Hoechst H33342 dye based confocal plate reader assay
|
Homo sapiens
|
3.162
nM
|
|
Journal : J Med Chem
Title : Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M<sub>2</sub> Receptor.
Year : 2020
Volume : 63
Issue : 8
First Page : 4133
Last Page : 4154
Authors : She X, Pegoli A, Gruber CG, Wifling D, Carpenter J, Hübner H, Chen M, Wan J, Bernhardt G, Gmeiner P, Holliday ND, Keller M.
Abstract : Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M<sub>2</sub>R affinities (p<i>K</i><sub>i</sub> (radioligand competition binding): 9.10-9.59). Binding studies at M<sub>1</sub> and M<sub>3</sub>-M<sub>5</sub> receptors indicated a M<sub>2</sub>R preference. Flow cytometric and high-content imaging saturation and competition binding (M<sub>1</sub>R, M<sub>2</sub>R, and M<sub>4</sub>R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM<sub>2</sub>R cells). Results from dissociation and saturation binding experiments (M<sub>2</sub>R) in the presence of allosteric M<sub>2</sub>R modulators (dissociation: W84, LY2119620, and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M<sub>2</sub>R in imaging and binding studies and suggest that they have a dualsteric mode of action.
|
Displacement of 4-(2-((1E,3E)-5-((E)-1-(6-((3,5-Bis((2-(3-(1-(4-(1-(2-oxo-2-(11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)ethyl)piperidin-4-yl)butyl)-1H-imidazol-4-yl)propanamido)ethyl)carbamoyl)benzyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-3,3-dimethyl-3H-indol-1-ium-1-yl)butane-1-sulfonate Tris(hydrotrifluoroacetate) fluorescent tracer from human muscarinic M2 receptor expressed in CHO-K9 cells measured after 60 mins by Hoechst H33342 dye based confocal plate reader assay
|
Homo sapiens
|
7.079
nM
|
|
Journal : J Med Chem
Title : Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M<sub>2</sub> Receptor.
Year : 2020
Volume : 63
Issue : 8
First Page : 4133
Last Page : 4154
Authors : She X, Pegoli A, Gruber CG, Wifling D, Carpenter J, Hübner H, Chen M, Wan J, Bernhardt G, Gmeiner P, Holliday ND, Keller M.
Abstract : Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M<sub>2</sub>R affinities (p<i>K</i><sub>i</sub> (radioligand competition binding): 9.10-9.59). Binding studies at M<sub>1</sub> and M<sub>3</sub>-M<sub>5</sub> receptors indicated a M<sub>2</sub>R preference. Flow cytometric and high-content imaging saturation and competition binding (M<sub>1</sub>R, M<sub>2</sub>R, and M<sub>4</sub>R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM<sub>2</sub>R cells). Results from dissociation and saturation binding experiments (M<sub>2</sub>R) in the presence of allosteric M<sub>2</sub>R modulators (dissociation: W84, LY2119620, and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M<sub>2</sub>R in imaging and binding studies and suggest that they have a dualsteric mode of action.
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Displacement of [3H]-NMS from human muscarinic M2 receptor expressed in CHO-K9 cells measured after 60 mins by Hoechst H33342 dye based confocal plate reader assay
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Homo sapiens
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0.912
nM
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Journal : J Med Chem
Title : Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M<sub>2</sub> Receptor.
Year : 2020
Volume : 63
Issue : 8
First Page : 4133
Last Page : 4154
Authors : She X, Pegoli A, Gruber CG, Wifling D, Carpenter J, Hübner H, Chen M, Wan J, Bernhardt G, Gmeiner P, Holliday ND, Keller M.
Abstract : Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M<sub>2</sub>R affinities (p<i>K</i><sub>i</sub> (radioligand competition binding): 9.10-9.59). Binding studies at M<sub>1</sub> and M<sub>3</sub>-M<sub>5</sub> receptors indicated a M<sub>2</sub>R preference. Flow cytometric and high-content imaging saturation and competition binding (M<sub>1</sub>R, M<sub>2</sub>R, and M<sub>4</sub>R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM<sub>2</sub>R cells). Results from dissociation and saturation binding experiments (M<sub>2</sub>R) in the presence of allosteric M<sub>2</sub>R modulators (dissociation: W84, LY2119620, and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M<sub>2</sub>R in imaging and binding studies and suggest that they have a dualsteric mode of action.
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Myorelaxant effect in Sprague-Dawley rat tracheal ring assessed as maximal relaxation of carbachol-induced smooth muscle contraction by organ bath assay
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Rattus norvegicus
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0.98
nM
|
|
