|
Percent inhibition of Forskolin-Induced cAMP production in A9 L cells expressing m2 receptors
|
Mus musculus
|
44.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological characterization of 1,4,5,6-tetrahydropyrimidine and 2-amino-3,4,5,6-tetrahydropyridine derivatives as selective m1 agonists.
Year : 1997
Volume : 40
Issue : 8
First Page : 1230
Last Page : 1246
Authors : Messer WS, Abuh YF, Liu Y, Periyasamy S, Ngur DO, Edgar MA, El-Assadi AA, Sbeih S, Dunbar PG, Roknich S, Rho T, Fang Z, Ojo B, Zhang H, Huzl JJ, Nagy PI.
Abstract : Previous studies identified several novel tetrahydropyrimidine derivatives exhibiting muscarinic agonist activity in rat brain. Such compounds might be useful in treating cognitive and memory deficits associated with low acetylcholine levels, as found in Alzheimer's disease. To determine the molecular features of ligands important for binding and activity at muscarinic receptor subtypes, the series of tetrahydropyrimidines was extended. Several active compounds were examined further for functional selectivity through biochemical studies of muscarinic receptor activity using receptor subtypes expressed in cell lines. Several amidine derivatives displayed high efficacy at m1 receptors and lower activity at m3 receptors coupled to phosphoinositide (PI) metabolism in A9 L cells. Four ligands, including 1b, 1f, 2b, and 7b, exhibited marked functional selectivity for m1 vs m3 receptors. Compound 1f also exhibited low activity at m2 receptors coupled to the inhibition of adenylyl cyclase in A9 L cells. Molecular modeling studies also were initiated to help understand the nature of the interaction of muscarinic agonists with the m1 receptor using a nine amino model of the m1 receptor. Several important interactions were identified, including interactions between the ester moiety and Thr192. Additional interactions were found for oxadiazoles and alkynyl derivatives with Asn382, suggesting that enhanced potency and selectivity may be achieved by maximizing interactions with Asp105, Thr192, and Asn382. Taken together, the data indicate that several amidine derivatives display functional selectivity for m1 muscarinic receptors, warranting further evaluation as therapeutic agents for the treatment of Alzheimer's disease. In addition, several amino acid residues were identified as potential binding sites for m1 agonists. These data may be useful in directing efforts to develop even more selective m1 agonists.
|
Agonistic activity against M1 muscarinic receptor expressed in A9 L cells.
|
None
|
57.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological characterization of bivalent 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as selective muscarinic agonists.
Year : 2001
Volume : 44
Issue : 26
First Page : 4563
Last Page : 4576
Authors : Rajeswaran WG, Cao Y, Huang XP, Wroblewski ME, Colclough T, Lee S, Liu F, Nagy PI, Ellis J, Levine BA, Nocka KH, Messer WS.
Abstract : Selective muscarinic agonists could be useful in the treatment of neurological disorders such as Alzheimer's disease, schizophrenia, and chronic pain. Many muscarinic agonists have been developed, yet most exhibit at best limited functional selectivity for a given receptor subtype perhaps because of the high degree of sequence homology within the putative binding site, which appears to be buried within the transmembrane domains. Bivalent compounds containing essentially two agonist pharmacophores within the same molecule were synthesized and tested for receptor binding affinity and muscarinic agonist activity. A series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine linked by an alkyloxy moiety exhibited very high affinity (K(i) < 1 nM) and strong agonist activity. The degree of activity depended on the length of the linking alkyl group, which could be replaced by a poly(ethylene glycol) moiety, resulting in improved water solubility, binding affinity, and agonist potency.
|
Binding affinity towards M1 muscarinic receptor expressed in A9 L cells by displacing [3H](R)-QNB radioligand.
|
None
|
82.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological characterization of bivalent 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as selective muscarinic agonists.
Year : 2001
Volume : 44
Issue : 26
First Page : 4563
Last Page : 4576
Authors : Rajeswaran WG, Cao Y, Huang XP, Wroblewski ME, Colclough T, Lee S, Liu F, Nagy PI, Ellis J, Levine BA, Nocka KH, Messer WS.
Abstract : Selective muscarinic agonists could be useful in the treatment of neurological disorders such as Alzheimer's disease, schizophrenia, and chronic pain. Many muscarinic agonists have been developed, yet most exhibit at best limited functional selectivity for a given receptor subtype perhaps because of the high degree of sequence homology within the putative binding site, which appears to be buried within the transmembrane domains. Bivalent compounds containing essentially two agonist pharmacophores within the same molecule were synthesized and tested for receptor binding affinity and muscarinic agonist activity. A series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine linked by an alkyloxy moiety exhibited very high affinity (K(i) < 1 nM) and strong agonist activity. The degree of activity depended on the length of the linking alkyl group, which could be replaced by a poly(ethylene glycol) moiety, resulting in improved water solubility, binding affinity, and agonist potency.
|
Effective concentration was evaluated against Muscarinic acetylcholine receptor M1 expressed in A9 L cells
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological characterization of 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as muscarinic agonists for the treatment of neurological disorders.
Year : 2003
Volume : 46
Issue : 20
First Page : 4273
Last Page : 4286
Authors : Cao Y, Zhang M, Wu C, Lee S, Wroblewski ME, Whipple T, Nagy PI, Takács-Novák K, Balázs A, Torös S, Messer WS.
Abstract : Muscarinic agonists might be useful in the treatment of neurological disorders, including Alzheimer's disease, schizophrenia, chronic pain, and drug abuse. Previous studies identified a series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine with high activity and selectivity for muscarinic receptors. To develop compounds with improved central nervous system penetration, several new derivatives were synthesized and characterized for muscarinic receptor binding and activity. One ligand (11) exhibited agonist activity at M(1), M(2), and M(4) receptors, a selectivity profile suggesting potential utility in the treatment of schizophrenia.
|
Inhibition of [3H](R)-QNB to Muscarinic acetylcholine receptor M1 expressed in A9 L cells
|
Homo sapiens
|
158.49
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological characterization of 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as muscarinic agonists for the treatment of neurological disorders.
Year : 2003
Volume : 46
Issue : 20
First Page : 4273
Last Page : 4286
Authors : Cao Y, Zhang M, Wu C, Lee S, Wroblewski ME, Whipple T, Nagy PI, Takács-Novák K, Balázs A, Torös S, Messer WS.
Abstract : Muscarinic agonists might be useful in the treatment of neurological disorders, including Alzheimer's disease, schizophrenia, chronic pain, and drug abuse. Previous studies identified a series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine with high activity and selectivity for muscarinic receptors. To develop compounds with improved central nervous system penetration, several new derivatives were synthesized and characterized for muscarinic receptor binding and activity. One ligand (11) exhibited agonist activity at M(1), M(2), and M(4) receptors, a selectivity profile suggesting potential utility in the treatment of schizophrenia.
|
Stimulation of phosphoinositol hydrolysis in the mouse fibroblast cell line A9L-M1 expressing Muscarinic acetylcholine receptor M1.
|
Mus musculus
|
134.5
nM
|
|
Journal : J. Med. Chem.
Title : 1-(1,2,5-Thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]heptanes as new potent muscarinic M1 agonists: structure-activity relationship for 3-aryl-2-propyn-1-yloxy and 3-aryl-2-propyn-1-ylthio derivatives.
Year : 1999
Volume : 42
Issue : 11
First Page : 1999
Last Page : 2006
Authors : Jeppesen L, Olesen PH, Hansen L, Sheardown MJ, Thomsen C, Rasmussen T, Jensen AF, Christensen MS, Rimvall K, Ward JS, Whitesitt C, Calligaro DO, Bymaster FP, Delapp NW, Felder CC, Shannon HE, Sauerberg P.
Abstract : Two new series of 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2, 6)]heptanes were synthesized and evaluated for their in vitro activity in cell lines transfected with either the human M1 or M2 receptor. 3-Phenyl-2-propyn-1-yloxy and -1-ylthio analogues substituted with halogen in the meta position showed high functional potency, efficacy, and selectivity toward the M1 receptor subtype. A quite unique functional M1 receptor selectivity was observed for compounds 8b, 8d, 8f, 9b, 9d, and 9f. Bioavailability studies in rats indicated an oral bioavailability of about 20-30%, with the N-oxide as the only detected metabolite.
|
Binding affinity for muscarinic acetylcholine receptor M1 using [3H]pirenzepine (Pz) radioligand in rat hippocampus membranes.
|
None
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : 1,2,5-Thiadiazole analogues of aceclidine as potent m1 muscarinic agonists.
Year : 1998
Volume : 41
Issue : 3
First Page : 379
Last Page : 392
Authors : Ward JS, Merritt L, Calligaro DO, Bymaster FP, Shannon HE, Mitch CH, Whitesitt C, Brunsting D, Sheardown MJ, Olesen PH, Swedberg MD, Jeppesen L, Sauerberg P.
Abstract : The acetyl group of the muscarinic agonist aceclidine 4 was replaced by various 1,2,5-thiadiazoles to provide a new series of potent m1 muscarinic agonists 17 and 18. Optimal m1 muscarinic agonist potency was achieved when the 1,2,5-thiadiazole substituent was either a butyloxy, 17d, or butylthio, 18d, group. Although 1,2,5-oxadiazole 37 and pyrazine 39 are iso-pi-electronic with 1,2,5-thiadiazole 17d, both analogues were substantially less active than 17d. Compounds with high muscarinic affinity and/or m1 muscarinic agonist efficacy were also obtained when the 3-oxyquinuclidine moiety of 17d or 18c was replaced by ethanolamines, hydroxypyrrolidines, hydroxyazetidine, hydroxyisotropanes, or hydroxyazanorbornanes. The structure-activity data support the participation of the oxygen or sulfur atom in the substituent on the 1,2,5-thiadiazole in the activation of the m1 receptor. Several of these new 1,2,5-thiadiazoles have m1 agonist efficacy, potency, and selectivity comparable to those of xanomeline 2 in the muscarinic tests investigated.
|
Binding affinity for muscarinic acetylcholine receptor M1 using [3H]oxotremorine-M (Oxo-M) radioligand in rat hippocampus membranes
|
None
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : 1,2,5-Thiadiazole analogues of aceclidine as potent m1 muscarinic agonists.
Year : 1998
Volume : 41
Issue : 3
First Page : 379
Last Page : 392
Authors : Ward JS, Merritt L, Calligaro DO, Bymaster FP, Shannon HE, Mitch CH, Whitesitt C, Brunsting D, Sheardown MJ, Olesen PH, Swedberg MD, Jeppesen L, Sauerberg P.
Abstract : The acetyl group of the muscarinic agonist aceclidine 4 was replaced by various 1,2,5-thiadiazoles to provide a new series of potent m1 muscarinic agonists 17 and 18. Optimal m1 muscarinic agonist potency was achieved when the 1,2,5-thiadiazole substituent was either a butyloxy, 17d, or butylthio, 18d, group. Although 1,2,5-oxadiazole 37 and pyrazine 39 are iso-pi-electronic with 1,2,5-thiadiazole 17d, both analogues were substantially less active than 17d. Compounds with high muscarinic affinity and/or m1 muscarinic agonist efficacy were also obtained when the 3-oxyquinuclidine moiety of 17d or 18c was replaced by ethanolamines, hydroxypyrrolidines, hydroxyazetidine, hydroxyisotropanes, or hydroxyazanorbornanes. The structure-activity data support the participation of the oxygen or sulfur atom in the substituent on the 1,2,5-thiadiazole in the activation of the m1 receptor. Several of these new 1,2,5-thiadiazoles have m1 agonist efficacy, potency, and selectivity comparable to those of xanomeline 2 in the muscarinic tests investigated.
|
Displacement of [3H]oxotremorine-M (Oxo-M) from rat hippocampus muscarinic acetylcholine receptor M1
|
Rattus norvegicus
|
9.7
nM
|
|
Journal : J. Med. Chem.
Title : Novel functional M1 selective muscarinic agonists. 2. Synthesis and structure-activity relationships of 3-pyrazinyl-1,2,5,6-tetrahydro-1-methylpyridines. Construction of a molecular model for the M1 pharmacophore.
Year : 1992
Volume : 35
Issue : 22
First Page : 4011
Last Page : 4019
Authors : Ward JS, Merritt L, Klimkowski VJ, Lamb ML, Mitch CH, Bymaster FP, Sawyer B, Shannon HE, Olesen PH, Honoré T.
Abstract : A series of 3-(3-substituted-pyrazinyl)-1,2,5,6-tetrahydro-1-methylpyridines were synthesized and found to have high affinity for central muscarinic receptors. The ability of some of these compounds to inhibit the electrically stimulated twitch of the guinea pig vas deferens indicated that the compounds were M1 agonists. M1 agonist activity was related to the length of the side chain attached to the pyrazine ring, with maximal activity being obtained with the hexyloxy side chain. The (hexyloxy)pyrazine 3f lacked M2 agonist activity as it failed to affect the guinea pig atria and was also relatively devoid of M3 agonist activity as determined by its lack of tremorogenic and sialogogic effects in mice. A comparison of the M1 agonist efficacy of these pyrazines and related 1,2,5-thiadiazoles and 1,2,5-oxadiazoles suggested that M1 efficacy was related to the magnitude of electrostatic potential located over the nitrogens of the respective heterocycles. The heteroatom directly attached to the 3 position of the pyrazine or 1,2,5-thiadiazole heterocycle markedly influenced the M1 efficacy of the compounds by determining the energetically favorably conformers for rotation about the bond connecting the tetrahydropyridyl ring and the heterocycle. A three-dimensional model for the M1-activating pharmacophore was proposed based on computational studies and the model of the muscarinic pharmacophore proposed by Schulman.
|
Displacement of [3H]pirenzepine (Pz) from rat hippocampus muscarinic acetylcholine receptor M1
|
Rattus norvegicus
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel functional M1 selective muscarinic agonists. 2. Synthesis and structure-activity relationships of 3-pyrazinyl-1,2,5,6-tetrahydro-1-methylpyridines. Construction of a molecular model for the M1 pharmacophore.
Year : 1992
Volume : 35
Issue : 22
First Page : 4011
Last Page : 4019
Authors : Ward JS, Merritt L, Klimkowski VJ, Lamb ML, Mitch CH, Bymaster FP, Sawyer B, Shannon HE, Olesen PH, Honoré T.
Abstract : A series of 3-(3-substituted-pyrazinyl)-1,2,5,6-tetrahydro-1-methylpyridines were synthesized and found to have high affinity for central muscarinic receptors. The ability of some of these compounds to inhibit the electrically stimulated twitch of the guinea pig vas deferens indicated that the compounds were M1 agonists. M1 agonist activity was related to the length of the side chain attached to the pyrazine ring, with maximal activity being obtained with the hexyloxy side chain. The (hexyloxy)pyrazine 3f lacked M2 agonist activity as it failed to affect the guinea pig atria and was also relatively devoid of M3 agonist activity as determined by its lack of tremorogenic and sialogogic effects in mice. A comparison of the M1 agonist efficacy of these pyrazines and related 1,2,5-thiadiazoles and 1,2,5-oxadiazoles suggested that M1 efficacy was related to the magnitude of electrostatic potential located over the nitrogens of the respective heterocycles. The heteroatom directly attached to the 3 position of the pyrazine or 1,2,5-thiadiazole heterocycle markedly influenced the M1 efficacy of the compounds by determining the energetically favorably conformers for rotation about the bond connecting the tetrahydropyridyl ring and the heterocycle. A three-dimensional model for the M1-activating pharmacophore was proposed based on computational studies and the model of the muscarinic pharmacophore proposed by Schulman.
|
In vitro binding affinity towards Muscarinic acetylcholine receptor M1 by the displacement of [3H]oxotremorine-M in rat brain membranes
|
None
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure activity relationships of alkyl substituted analogues of the functional M1 selective muscarinic receptor agonist xanomeline
Year : 1994
Volume : 4
Issue : 18
First Page : 2205
Last Page : 2210
Authors : Quimby SJ, Shannon HE, Bymaster FP, Sauerberg P, Olesen PH, Sheardown MJ, Suzdak PD, Mitch CH
|
In vitro binding affinity towards Muscarinic acetylcholine receptor M1 by the displacement of [3H]pirenzepine in rat cerebral cortical membranes
|
None
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure activity relationships of alkyl substituted analogues of the functional M1 selective muscarinic receptor agonist xanomeline
Year : 1994
Volume : 4
Issue : 18
First Page : 2205
Last Page : 2210
Authors : Quimby SJ, Shannon HE, Bymaster FP, Sauerberg P, Olesen PH, Sheardown MJ, Suzdak PD, Mitch CH
|
Binding activity against muscarinic acetylcholine receptor M1 in rat brain, using [3H]OXO-M as the radioligand.
|
None
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Functionally selective M1 muscarinic agonists. 3. Side chains and azacycles contributing to functional muscarinic selectivity among pyrazinylazacycles.
Year : 1995
Volume : 38
Issue : 18
First Page : 3469
Last Page : 3481
Authors : Ward JS, Merritt L, Calligaro DO, Bymaster FP, Shannon HE, Sawyer BD, Mitch CH, Deeter JB, Peters SC, Sheardown MJ, Olesen PH, Swedberg MD, Sauerberg P.
Abstract : In an attempt to improve upon the M1 agonist activity of the selective M1 agonist xanomeline and related compounds, the M1 muscarinic efficacies and potencies of 3- and 6-substituted pyrazinylazacycles were varied by changing both the 3- and 6-substituents as well as the azacycle. Significant improvements in efficacy and potency over the previously prepared [3-(hexyloxy)pyrazinyl]tetrahydropyridine 19 were obtained with the [3-(hexyloxy)pyrazinyl]-quinuclidine 5i. The M1 activity of 5i showed some enantioselectivity with (S)-5i being ca. 4-fold more potent than (R)-5i. Like 19 and xanomeline, 5i was a functionally selective M1 agonist that showed greater functional selectivity than widely studied pyrazinylquinuclidine 5n (L-689,660). The improved functional selectivity of 5i over 5n could be attributed to the additional binding interactions between the hexyloxy side chain of 5i and the M1 receptor that are not available to 5n. Although 5i may show M1 functional selectivity comparable to xanomeliine, 5i is a less efficacious and potent M1 agonist than xanomeline.
|
Binding activity against muscarinic acetylcholine receptor M1 in rat brain, using [3H]-Pz as the radioligand.
|
None
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Functionally selective M1 muscarinic agonists. 3. Side chains and azacycles contributing to functional muscarinic selectivity among pyrazinylazacycles.
Year : 1995
Volume : 38
Issue : 18
First Page : 3469
Last Page : 3481
Authors : Ward JS, Merritt L, Calligaro DO, Bymaster FP, Shannon HE, Sawyer BD, Mitch CH, Deeter JB, Peters SC, Sheardown MJ, Olesen PH, Swedberg MD, Sauerberg P.
Abstract : In an attempt to improve upon the M1 agonist activity of the selective M1 agonist xanomeline and related compounds, the M1 muscarinic efficacies and potencies of 3- and 6-substituted pyrazinylazacycles were varied by changing both the 3- and 6-substituents as well as the azacycle. Significant improvements in efficacy and potency over the previously prepared [3-(hexyloxy)pyrazinyl]tetrahydropyridine 19 were obtained with the [3-(hexyloxy)pyrazinyl]-quinuclidine 5i. The M1 activity of 5i showed some enantioselectivity with (S)-5i being ca. 4-fold more potent than (R)-5i. Like 19 and xanomeline, 5i was a functionally selective M1 agonist that showed greater functional selectivity than widely studied pyrazinylquinuclidine 5n (L-689,660). The improved functional selectivity of 5i over 5n could be attributed to the additional binding interactions between the hexyloxy side chain of 5i and the M1 receptor that are not available to 5n. Although 5i may show M1 functional selectivity comparable to xanomeliine, 5i is a less efficacious and potent M1 agonist than xanomeline.
|
Compound was tested for binding inhibition of [3H](R)-QNB to Muscarinic acetylcholine receptor M3 expressed in A9 L cells
|
None
|
79.43
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological characterization of 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as muscarinic agonists for the treatment of neurological disorders.
Year : 2003
Volume : 46
Issue : 20
First Page : 4273
Last Page : 4286
Authors : Cao Y, Zhang M, Wu C, Lee S, Wroblewski ME, Whipple T, Nagy PI, Takács-Novák K, Balázs A, Torös S, Messer WS.
Abstract : Muscarinic agonists might be useful in the treatment of neurological disorders, including Alzheimer's disease, schizophrenia, chronic pain, and drug abuse. Previous studies identified a series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine with high activity and selectivity for muscarinic receptors. To develop compounds with improved central nervous system penetration, several new derivatives were synthesized and characterized for muscarinic receptor binding and activity. One ligand (11) exhibited agonist activity at M(1), M(2), and M(4) receptors, a selectivity profile suggesting potential utility in the treatment of schizophrenia.
|
Effective concentration required for stimulation of phosphoinositol (PI) hydrolysis in the A9 L cell line transfected with the Muscarinic acetylcholine receptor M1.
|
None
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : 1,2,5-Thiadiazole analogues of aceclidine as potent m1 muscarinic agonists.
Year : 1998
Volume : 41
Issue : 3
First Page : 379
Last Page : 392
Authors : Ward JS, Merritt L, Calligaro DO, Bymaster FP, Shannon HE, Mitch CH, Whitesitt C, Brunsting D, Sheardown MJ, Olesen PH, Swedberg MD, Jeppesen L, Sauerberg P.
Abstract : The acetyl group of the muscarinic agonist aceclidine 4 was replaced by various 1,2,5-thiadiazoles to provide a new series of potent m1 muscarinic agonists 17 and 18. Optimal m1 muscarinic agonist potency was achieved when the 1,2,5-thiadiazole substituent was either a butyloxy, 17d, or butylthio, 18d, group. Although 1,2,5-oxadiazole 37 and pyrazine 39 are iso-pi-electronic with 1,2,5-thiadiazole 17d, both analogues were substantially less active than 17d. Compounds with high muscarinic affinity and/or m1 muscarinic agonist efficacy were also obtained when the 3-oxyquinuclidine moiety of 17d or 18c was replaced by ethanolamines, hydroxypyrrolidines, hydroxyazetidine, hydroxyisotropanes, or hydroxyazanorbornanes. The structure-activity data support the participation of the oxygen or sulfur atom in the substituent on the 1,2,5-thiadiazole in the activation of the m1 receptor. Several of these new 1,2,5-thiadiazoles have m1 agonist efficacy, potency, and selectivity comparable to those of xanomeline 2 in the muscarinic tests investigated.
|
Inhibitory activity was evaluated against Muscarinic acetylcholine receptor M4 expressed in A9 L cells
|
None
|
25.12
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological characterization of 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as muscarinic agonists for the treatment of neurological disorders.
Year : 2003
Volume : 46
Issue : 20
First Page : 4273
Last Page : 4286
Authors : Cao Y, Zhang M, Wu C, Lee S, Wroblewski ME, Whipple T, Nagy PI, Takács-Novák K, Balázs A, Torös S, Messer WS.
Abstract : Muscarinic agonists might be useful in the treatment of neurological disorders, including Alzheimer's disease, schizophrenia, chronic pain, and drug abuse. Previous studies identified a series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine with high activity and selectivity for muscarinic receptors. To develop compounds with improved central nervous system penetration, several new derivatives were synthesized and characterized for muscarinic receptor binding and activity. One ligand (11) exhibited agonist activity at M(1), M(2), and M(4) receptors, a selectivity profile suggesting potential utility in the treatment of schizophrenia.
|
Compound was tested for binding inhibition of [3H](R)-QNB to Muscarinic acetylcholine receptor M4 expressed in A9 L cells
|
None
|
39.81
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological characterization of 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as muscarinic agonists for the treatment of neurological disorders.
Year : 2003
Volume : 46
Issue : 20
First Page : 4273
Last Page : 4286
Authors : Cao Y, Zhang M, Wu C, Lee S, Wroblewski ME, Whipple T, Nagy PI, Takács-Novák K, Balázs A, Torös S, Messer WS.
Abstract : Muscarinic agonists might be useful in the treatment of neurological disorders, including Alzheimer's disease, schizophrenia, chronic pain, and drug abuse. Previous studies identified a series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine with high activity and selectivity for muscarinic receptors. To develop compounds with improved central nervous system penetration, several new derivatives were synthesized and characterized for muscarinic receptor binding and activity. One ligand (11) exhibited agonist activity at M(1), M(2), and M(4) receptors, a selectivity profile suggesting potential utility in the treatment of schizophrenia.
|
Compound was tested for its potency towards Muscarinic acetylcholine receptor M2 by inhibiting forskolin induced c-AMP formation in CHO-M2 cells
|
None
|
398.0
nM
|
|
Journal : J. Med. Chem.
Title : 1-(1,2,5-Thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]heptanes as new potent muscarinic M1 agonists: structure-activity relationship for 3-aryl-2-propyn-1-yloxy and 3-aryl-2-propyn-1-ylthio derivatives.
Year : 1999
Volume : 42
Issue : 11
First Page : 1999
Last Page : 2006
Authors : Jeppesen L, Olesen PH, Hansen L, Sheardown MJ, Thomsen C, Rasmussen T, Jensen AF, Christensen MS, Rimvall K, Ward JS, Whitesitt C, Calligaro DO, Bymaster FP, Delapp NW, Felder CC, Shannon HE, Sauerberg P.
Abstract : Two new series of 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2, 6)]heptanes were synthesized and evaluated for their in vitro activity in cell lines transfected with either the human M1 or M2 receptor. 3-Phenyl-2-propyn-1-yloxy and -1-ylthio analogues substituted with halogen in the meta position showed high functional potency, efficacy, and selectivity toward the M1 receptor subtype. A quite unique functional M1 receptor selectivity was observed for compounds 8b, 8d, 8f, 9b, 9d, and 9f. Bioavailability studies in rats indicated an oral bioavailability of about 20-30%, with the N-oxide as the only detected metabolite.
|
Inhibitory activity was evaluated against Muscarinic acetylcholine receptor M2 expressed in A9 L cells
|
None
|
12.59
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological characterization of 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as muscarinic agonists for the treatment of neurological disorders.
Year : 2003
Volume : 46
Issue : 20
First Page : 4273
Last Page : 4286
Authors : Cao Y, Zhang M, Wu C, Lee S, Wroblewski ME, Whipple T, Nagy PI, Takács-Novák K, Balázs A, Torös S, Messer WS.
Abstract : Muscarinic agonists might be useful in the treatment of neurological disorders, including Alzheimer's disease, schizophrenia, chronic pain, and drug abuse. Previous studies identified a series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine with high activity and selectivity for muscarinic receptors. To develop compounds with improved central nervous system penetration, several new derivatives were synthesized and characterized for muscarinic receptor binding and activity. One ligand (11) exhibited agonist activity at M(1), M(2), and M(4) receptors, a selectivity profile suggesting potential utility in the treatment of schizophrenia.
|
Affinity towards human M1 receptor expressed in CHO cells using [3H]QNB as radioligand
|
None
|
42.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a highly potent, functionally-selective muscarinic M1 agonist, WAY-132983 using rational drug design and receptor modelling.
Year : 1999
Volume : 9
Issue : 14
First Page : 1895
Last Page : 1900
Authors : Sabb AL, Husbands GM, Tokolics J, Stein RP, Tasse RP, Boast CA, Moyer JA, Abou-Gharbia M.
Abstract : Rational drug design utilizing a receptor homology model of the human muscarinic M1 receptor led to the discovery of the highly potent (Ki = 2 nM), efficacious, and in vivo functionally-selective M1 agonist, WAY-132983.
|
Compound was tested for binding inhibition of [3H](R)-QNB to Muscarinic acetylcholine receptor M2 expressed in A9 L cells
|
None
|
50.12
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological characterization of 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as muscarinic agonists for the treatment of neurological disorders.
Year : 2003
Volume : 46
Issue : 20
First Page : 4273
Last Page : 4286
Authors : Cao Y, Zhang M, Wu C, Lee S, Wroblewski ME, Whipple T, Nagy PI, Takács-Novák K, Balázs A, Torös S, Messer WS.
Abstract : Muscarinic agonists might be useful in the treatment of neurological disorders, including Alzheimer's disease, schizophrenia, chronic pain, and drug abuse. Previous studies identified a series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine with high activity and selectivity for muscarinic receptors. To develop compounds with improved central nervous system penetration, several new derivatives were synthesized and characterized for muscarinic receptor binding and activity. One ligand (11) exhibited agonist activity at M(1), M(2), and M(4) receptors, a selectivity profile suggesting potential utility in the treatment of schizophrenia.
|
Displacement of [3H]-Pz (pirenzepine) from the muscarinic receptor M1 of the rat hippocampus
|
Rattus norvegicus
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of heterocyclic analogues of the functional M1 selective muscarinic agonist hexyloxy-TZTP
Year : 1992
Volume : 2
Issue : 8
First Page : 809
Last Page : 814
Authors : Sauerberg P, Olesen PH, Suzdak PD, Sheardown MJ, Mitch CH, Sawyer BD, Shannon HE
|
In vitro Muscarinic acetylcholine receptor M2 binding was evaluated in rat brain membranes by using [3H]- Oxo-M
|
None
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : 1-(1,2,5-Thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]heptanes as new potent muscarinic M1 agonists: structure-activity relationship for 3-aryl-2-propyn-1-yloxy and 3-aryl-2-propyn-1-ylthio derivatives.
Year : 1999
Volume : 42
Issue : 11
First Page : 1999
Last Page : 2006
Authors : Jeppesen L, Olesen PH, Hansen L, Sheardown MJ, Thomsen C, Rasmussen T, Jensen AF, Christensen MS, Rimvall K, Ward JS, Whitesitt C, Calligaro DO, Bymaster FP, Delapp NW, Felder CC, Shannon HE, Sauerberg P.
Abstract : Two new series of 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2, 6)]heptanes were synthesized and evaluated for their in vitro activity in cell lines transfected with either the human M1 or M2 receptor. 3-Phenyl-2-propyn-1-yloxy and -1-ylthio analogues substituted with halogen in the meta position showed high functional potency, efficacy, and selectivity toward the M1 receptor subtype. A quite unique functional M1 receptor selectivity was observed for compounds 8b, 8d, 8f, 9b, 9d, and 9f. Bioavailability studies in rats indicated an oral bioavailability of about 20-30%, with the N-oxide as the only detected metabolite.
|
Displacement of [3H]-OXO-M (oxotremorine-M) from the central muscarinic receptor sites of the rat brain membranes
|
Rattus norvegicus
|
9.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of heterocyclic analogues of the functional M1 selective muscarinic agonist hexyloxy-TZTP
Year : 1992
Volume : 2
Issue : 8
First Page : 809
Last Page : 814
Authors : Sauerberg P, Olesen PH, Suzdak PD, Sheardown MJ, Mitch CH, Sawyer BD, Shannon HE
|
Percent maximum inhibition of the twitch response in the electrically stimulated rabbit vas deferens was determined.
|
Oryctolagus cuniculus
|
88.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of heterocyclic analogues of the functional M1 selective muscarinic agonist hexyloxy-TZTP
Year : 1992
Volume : 2
Issue : 8
First Page : 809
Last Page : 814
Authors : Sauerberg P, Olesen PH, Suzdak PD, Sheardown MJ, Mitch CH, Sawyer BD, Shannon HE
|
Compound was evaluated for the inhibition of the twitch response in the electrically stimulated rabbit vas deferens
|
Oryctolagus cuniculus
|
0.01
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of heterocyclic analogues of the functional M1 selective muscarinic agonist hexyloxy-TZTP
Year : 1992
Volume : 2
Issue : 8
First Page : 809
Last Page : 814
Authors : Sauerberg P, Olesen PH, Suzdak PD, Sheardown MJ, Mitch CH, Sawyer BD, Shannon HE
|
Efficacy at muscarinic acetylcholine receptor M1 measured by the ability to inhibit the electrically stimulated twitch of the rabbit vas deferens
|
Oryctolagus cuniculus
|
0.008
nM
|
|
Journal : J. Med. Chem.
Title : Novel functional M1 selective muscarinic agonists. 2. Synthesis and structure-activity relationships of 3-pyrazinyl-1,2,5,6-tetrahydro-1-methylpyridines. Construction of a molecular model for the M1 pharmacophore.
Year : 1992
Volume : 35
Issue : 22
First Page : 4011
Last Page : 4019
Authors : Ward JS, Merritt L, Klimkowski VJ, Lamb ML, Mitch CH, Bymaster FP, Sawyer B, Shannon HE, Olesen PH, Honoré T.
Abstract : A series of 3-(3-substituted-pyrazinyl)-1,2,5,6-tetrahydro-1-methylpyridines were synthesized and found to have high affinity for central muscarinic receptors. The ability of some of these compounds to inhibit the electrically stimulated twitch of the guinea pig vas deferens indicated that the compounds were M1 agonists. M1 agonist activity was related to the length of the side chain attached to the pyrazine ring, with maximal activity being obtained with the hexyloxy side chain. The (hexyloxy)pyrazine 3f lacked M2 agonist activity as it failed to affect the guinea pig atria and was also relatively devoid of M3 agonist activity as determined by its lack of tremorogenic and sialogogic effects in mice. A comparison of the M1 agonist efficacy of these pyrazines and related 1,2,5-thiadiazoles and 1,2,5-oxadiazoles suggested that M1 efficacy was related to the magnitude of electrostatic potential located over the nitrogens of the respective heterocycles. The heteroatom directly attached to the 3 position of the pyrazine or 1,2,5-thiadiazole heterocycle markedly influenced the M1 efficacy of the compounds by determining the energetically favorably conformers for rotation about the bond connecting the tetrahydropyridyl ring and the heterocycle. A three-dimensional model for the M1-activating pharmacophore was proposed based on computational studies and the model of the muscarinic pharmacophore proposed by Schulman.
|
Binding affinity against muscarinic receptor in rat brain membranes using oxotremorine-M as ligand
|
None
|
9.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of side chains on 1,2,5-thiadiazole-azacycles optimal for muscarinic m1 receptor activation.
Year : 1998
Volume : 8
Issue : 20
First Page : 2897
Last Page : 2902
Authors : Sauerberg P, Jeppesen L, Olesen PH, Sheardown MJ, Fink-Jensen A, Rasmussen T, Rimvall K, Shannon HE, Bymaster FP, DeLapp NW, Calligaro DO, Ward JS, Whitesitt CA, Thomsen C.
Abstract : Series of analogs to the functional m1 selective agonist, xanomeline (hexyloxy-TZTP), were evaluated for their in vitro m1 efficacy in cell lines transfected with the human m1 receptor. Systematic variation of the side chain and the azacyclic ring led to the discovery of potent muscarinic agonists with robust m1 efficacy, all having the phenylpropargyloxy/thio as the side chain. The most selective compound was the phenylpropargylthio-[3.2.1] endo analog 28, which is a potent and efficacious m1 agonist with no m2 activity.
|
Inhibition of [3H](R)-QNB binding to human M1 receptor expressed in A9 L cells
|
Homo sapiens
|
158.49
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the binding and activity at muscarinic receptor subtypes and chimeras.
Year : 2006
Volume : 49
Issue : 25
First Page : 7518
Last Page : 7531
Authors : Tejada FR, Nagy PI, Xu M, Wu C, Katz T, Dorsey J, Rieman M, Lawlor E, Warrier M, Messer WS.
Abstract : As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.
|
Inhibition of [3H](R)-QNB binding to human M2 receptor expressed in A9 L cells
|
Homo sapiens
|
50.12
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the binding and activity at muscarinic receptor subtypes and chimeras.
Year : 2006
Volume : 49
Issue : 25
First Page : 7518
Last Page : 7531
Authors : Tejada FR, Nagy PI, Xu M, Wu C, Katz T, Dorsey J, Rieman M, Lawlor E, Warrier M, Messer WS.
Abstract : As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.
|
Inhibition of [3H](R)-QNB binding to human M3 receptor expressed in A9 L cells
|
Homo sapiens
|
79.43
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the binding and activity at muscarinic receptor subtypes and chimeras.
Year : 2006
Volume : 49
Issue : 25
First Page : 7518
Last Page : 7531
Authors : Tejada FR, Nagy PI, Xu M, Wu C, Katz T, Dorsey J, Rieman M, Lawlor E, Warrier M, Messer WS.
Abstract : As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.
|
Inhibition of [3H](R)-QNB binding to human M4 receptor expressed in A9 L cells
|
Homo sapiens
|
39.81
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the binding and activity at muscarinic receptor subtypes and chimeras.
Year : 2006
Volume : 49
Issue : 25
First Page : 7518
Last Page : 7531
Authors : Tejada FR, Nagy PI, Xu M, Wu C, Katz T, Dorsey J, Rieman M, Lawlor E, Warrier M, Messer WS.
Abstract : As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.
|
Agonist activity at human M1 receptor expressed in A9 L cells assessed as stimulation of phosphoinositide hydrolysis
|
Homo sapiens
|
316.23
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the binding and activity at muscarinic receptor subtypes and chimeras.
Year : 2006
Volume : 49
Issue : 25
First Page : 7518
Last Page : 7531
Authors : Tejada FR, Nagy PI, Xu M, Wu C, Katz T, Dorsey J, Rieman M, Lawlor E, Warrier M, Messer WS.
Abstract : As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.
|
Activity at human M4 receptor assessed as inhibition of forskolin-stimulated cAMP accumulation
|
Homo sapiens
|
25.12
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the binding and activity at muscarinic receptor subtypes and chimeras.
Year : 2006
Volume : 49
Issue : 25
First Page : 7518
Last Page : 7531
Authors : Tejada FR, Nagy PI, Xu M, Wu C, Katz T, Dorsey J, Rieman M, Lawlor E, Warrier M, Messer WS.
Abstract : As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.
|
Inhibition of [3H](R)-QNB binding to human M1/M5(o2) chimeric receptor expressed in A9 L cells
|
Homo sapiens
|
630.96
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the binding and activity at muscarinic receptor subtypes and chimeras.
Year : 2006
Volume : 49
Issue : 25
First Page : 7518
Last Page : 7531
Authors : Tejada FR, Nagy PI, Xu M, Wu C, Katz T, Dorsey J, Rieman M, Lawlor E, Warrier M, Messer WS.
Abstract : As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.
|
Inhibition of [3H](R)-QNB binding to human M1/M5(o3) chimeric receptor expressed in A9 L cells
|
Homo sapiens
|
501.19
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the binding and activity at muscarinic receptor subtypes and chimeras.
Year : 2006
Volume : 49
Issue : 25
First Page : 7518
Last Page : 7531
Authors : Tejada FR, Nagy PI, Xu M, Wu C, Katz T, Dorsey J, Rieman M, Lawlor E, Warrier M, Messer WS.
Abstract : As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.
|
Agonist activity at human M1/M5(o2) chimeric receptor expressed in A9 L cells assessed as stimulation of phosphoinositide hydrolysis
|
Homo sapiens
|
630.96
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the binding and activity at muscarinic receptor subtypes and chimeras.
Year : 2006
Volume : 49
Issue : 25
First Page : 7518
Last Page : 7531
Authors : Tejada FR, Nagy PI, Xu M, Wu C, Katz T, Dorsey J, Rieman M, Lawlor E, Warrier M, Messer WS.
Abstract : As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.
|
Agonist activity at human M1/M5(o2o3) chimeric receptor expressed in A9 L cells assessed as stimulation of phosphoinositide hydrolysis
|
Homo sapiens
|
316.23
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the binding and activity at muscarinic receptor subtypes and chimeras.
Year : 2006
Volume : 49
Issue : 25
First Page : 7518
Last Page : 7531
Authors : Tejada FR, Nagy PI, Xu M, Wu C, Katz T, Dorsey J, Rieman M, Lawlor E, Warrier M, Messer WS.
Abstract : As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.
|
Agonist activity at human M1 receptor E170K mutant expressed in A9 L cells assessed as stimulation of phosphoinositide hydrolysis
|
Homo sapiens
|
158.49
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the binding and activity at muscarinic receptor subtypes and chimeras.
Year : 2006
Volume : 49
Issue : 25
First Page : 7518
Last Page : 7531
Authors : Tejada FR, Nagy PI, Xu M, Wu C, Katz T, Dorsey J, Rieman M, Lawlor E, Warrier M, Messer WS.
Abstract : As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.
|
Agonist activity at human M1 receptor Q185E mutant expressed in A9 L cells assessed as stimulation of phosphoinositide hydrolysis
|
Homo sapiens
|
158.49
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the binding and activity at muscarinic receptor subtypes and chimeras.
Year : 2006
Volume : 49
Issue : 25
First Page : 7518
Last Page : 7531
Authors : Tejada FR, Nagy PI, Xu M, Wu C, Katz T, Dorsey J, Rieman M, Lawlor E, Warrier M, Messer WS.
Abstract : As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.
|
Displacement of [3H]NMS from human muscarinic M1 receptor expressed in CHO cells in continuous presence of radioligand
|
Homo sapiens
|
81.28
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of xanomeline analogs--probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor.
Year : 2008
Volume : 16
Issue : 3
First Page : 1376
Last Page : 1392
Authors : Kane BE, Grant MK, El-Fakahany EE, Ferguson DM.
Abstract : A series of xanomeline analogs were synthesized and evaluated for binding at the M(1) muscarinic acetylcholine receptor (M(1) receptor). Specifically, compounds that substitute the O-hexyl chain of xanomeline with polar, ionizable, or conformationally restricted moieties were assessed for their ability to bind to the M(1) receptor in a wash-resistant manner (persistent binding). From our screen, several novel ligands that persistently bind to the M(1) receptor with greater affinity than xanomeline were discovered. Results indicate that persistent binding may arise not only from hydrophobic interactions but also from ionic interactions with a secondary M(1) receptor binding site. Herein, a qualitative model that accounts for both binding scenarios is proposed and applied to understand the structural basis to wash-resistant binding and long-acting effects of xanomeline-based compounds.
|
Displacement of [3H]NMS from human muscarinic M1 receptor expressed in CHO cells at pH 6 in continuous presence of radioligand
|
Homo sapiens
|
18.2
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of xanomeline analogs--probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor.
Year : 2008
Volume : 16
Issue : 3
First Page : 1376
Last Page : 1392
Authors : Kane BE, Grant MK, El-Fakahany EE, Ferguson DM.
Abstract : A series of xanomeline analogs were synthesized and evaluated for binding at the M(1) muscarinic acetylcholine receptor (M(1) receptor). Specifically, compounds that substitute the O-hexyl chain of xanomeline with polar, ionizable, or conformationally restricted moieties were assessed for their ability to bind to the M(1) receptor in a wash-resistant manner (persistent binding). From our screen, several novel ligands that persistently bind to the M(1) receptor with greater affinity than xanomeline were discovered. Results indicate that persistent binding may arise not only from hydrophobic interactions but also from ionic interactions with a secondary M(1) receptor binding site. Herein, a qualitative model that accounts for both binding scenarios is proposed and applied to understand the structural basis to wash-resistant binding and long-acting effects of xanomeline-based compounds.
|
Displacement of [3H]NMS from human muscarinic M1 receptor expressed in CHO cells at pH 8 in continuous presence of radioligand
|
Homo sapiens
|
28.84
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of xanomeline analogs--probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor.
Year : 2008
Volume : 16
Issue : 3
First Page : 1376
Last Page : 1392
Authors : Kane BE, Grant MK, El-Fakahany EE, Ferguson DM.
Abstract : A series of xanomeline analogs were synthesized and evaluated for binding at the M(1) muscarinic acetylcholine receptor (M(1) receptor). Specifically, compounds that substitute the O-hexyl chain of xanomeline with polar, ionizable, or conformationally restricted moieties were assessed for their ability to bind to the M(1) receptor in a wash-resistant manner (persistent binding). From our screen, several novel ligands that persistently bind to the M(1) receptor with greater affinity than xanomeline were discovered. Results indicate that persistent binding may arise not only from hydrophobic interactions but also from ionic interactions with a secondary M(1) receptor binding site. Herein, a qualitative model that accounts for both binding scenarios is proposed and applied to understand the structural basis to wash-resistant binding and long-acting effects of xanomeline-based compounds.
|
Displacement of [3H]NMS from human muscarinic M1 receptor expressed in CHO cells at pH 8 by wash-resistant binding method
|
Homo sapiens
|
954.99
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of xanomeline analogs--probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor.
Year : 2008
Volume : 16
Issue : 3
First Page : 1376
Last Page : 1392
Authors : Kane BE, Grant MK, El-Fakahany EE, Ferguson DM.
Abstract : A series of xanomeline analogs were synthesized and evaluated for binding at the M(1) muscarinic acetylcholine receptor (M(1) receptor). Specifically, compounds that substitute the O-hexyl chain of xanomeline with polar, ionizable, or conformationally restricted moieties were assessed for their ability to bind to the M(1) receptor in a wash-resistant manner (persistent binding). From our screen, several novel ligands that persistently bind to the M(1) receptor with greater affinity than xanomeline were discovered. Results indicate that persistent binding may arise not only from hydrophobic interactions but also from ionic interactions with a secondary M(1) receptor binding site. Herein, a qualitative model that accounts for both binding scenarios is proposed and applied to understand the structural basis to wash-resistant binding and long-acting effects of xanomeline-based compounds.
|
Binding affinity to human cloned muscarinic M1 receptor expressed in CHO cells
|
Homo sapiens
|
7.943
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Docking analyses on human muscarinic receptors: unveiling the subtypes peculiarities in agonists binding.
Year : 2008
Volume : 16
Issue : 6
First Page : 3049
Last Page : 3058
Authors : Vistoli G, Pedretti A, Dei S, Scapecchi S, Marconi C, Romanelli MN.
Abstract : The study presents a docking analysis for the interaction capabilities of some muscarinic receptors (i.e., M(1), M(2), and M(5)) whose full-length models were previously generated by us. In detail, the docking simulations involved a dataset of 30 agonists, taken from the literature, including a first series of oxathiolane/dioxolane congeners and a second subset of more heterogeneous ligands. The obtained results unveil that it is possible to discriminate among the binding modes of considered muscarinic receptors, developing specific interaction patterns which are significantly different for the arrangement of both polar and hydrophobic interactions. Thus, the M(1) subtype possesses the widest binding site, while the M(2) receptor is characterized by a large but asymmetric region that accommodates the ligand's ammonium head and finally the M(5) binding site is quite similar to that of M(2) subtype being univocally characterized by a second aspartate residue which interacts with the ammonium head. The significant correlations between docking scores and affinity values afford an encouraging validation for the reported binding modes and confirm the key role of molecular flexibility in the ligand recognition of muscarinic receptors.
|
Binding affinity to human cloned muscarinic M2 receptor expressed in CHO cells
|
Homo sapiens
|
11.75
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Docking analyses on human muscarinic receptors: unveiling the subtypes peculiarities in agonists binding.
Year : 2008
Volume : 16
Issue : 6
First Page : 3049
Last Page : 3058
Authors : Vistoli G, Pedretti A, Dei S, Scapecchi S, Marconi C, Romanelli MN.
Abstract : The study presents a docking analysis for the interaction capabilities of some muscarinic receptors (i.e., M(1), M(2), and M(5)) whose full-length models were previously generated by us. In detail, the docking simulations involved a dataset of 30 agonists, taken from the literature, including a first series of oxathiolane/dioxolane congeners and a second subset of more heterogeneous ligands. The obtained results unveil that it is possible to discriminate among the binding modes of considered muscarinic receptors, developing specific interaction patterns which are significantly different for the arrangement of both polar and hydrophobic interactions. Thus, the M(1) subtype possesses the widest binding site, while the M(2) receptor is characterized by a large but asymmetric region that accommodates the ligand's ammonium head and finally the M(5) binding site is quite similar to that of M(2) subtype being univocally characterized by a second aspartate residue which interacts with the ammonium head. The significant correlations between docking scores and affinity values afford an encouraging validation for the reported binding modes and confirm the key role of molecular flexibility in the ligand recognition of muscarinic receptors.
|
Binding affinity to human cloned muscarinic M5 receptor expressed in CHO cells
|
Homo sapiens
|
15.14
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Docking analyses on human muscarinic receptors: unveiling the subtypes peculiarities in agonists binding.
Year : 2008
Volume : 16
Issue : 6
First Page : 3049
Last Page : 3058
Authors : Vistoli G, Pedretti A, Dei S, Scapecchi S, Marconi C, Romanelli MN.
Abstract : The study presents a docking analysis for the interaction capabilities of some muscarinic receptors (i.e., M(1), M(2), and M(5)) whose full-length models were previously generated by us. In detail, the docking simulations involved a dataset of 30 agonists, taken from the literature, including a first series of oxathiolane/dioxolane congeners and a second subset of more heterogeneous ligands. The obtained results unveil that it is possible to discriminate among the binding modes of considered muscarinic receptors, developing specific interaction patterns which are significantly different for the arrangement of both polar and hydrophobic interactions. Thus, the M(1) subtype possesses the widest binding site, while the M(2) receptor is characterized by a large but asymmetric region that accommodates the ligand's ammonium head and finally the M(5) binding site is quite similar to that of M(2) subtype being univocally characterized by a second aspartate residue which interacts with the ammonium head. The significant correlations between docking scores and affinity values afford an encouraging validation for the reported binding modes and confirm the key role of molecular flexibility in the ligand recognition of muscarinic receptors.
|
Agonist activity at human muscarinic M1 receptor expressed in CHO-K1 cells assessed as increase of acetylcholine-induced calcium flux by FLIPR assay
|
Homo sapiens
|
1.6
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.
|
Agonist activity at human muscarinic M3 receptor expressed in BHK-21 cells assessed as increase of acetylcholine-induced calcium flux by FLIPR assay
|
Homo sapiens
|
120.0
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.
|
Agonist activity at human muscarinic M4 receptor expressed in BHK-21 cells coexpressing Galpha16 subunit assessed as increase of acetylcholine-induced calcium flux by FLIPR assay
|
Homo sapiens
|
6.2
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.
|
Agonist activity at human muscarinic M5 receptor expressed in BHK-21 cells assessed as increase of acetylcholine-induced calcium flux by FLIPR assay
|
Homo sapiens
|
140.0
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]-AFDX-384 from human muscarinic M2 receptor expressed in CHO-K1 cells
|
Homo sapiens
|
120.0
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 M3 receptor expressed in BHK-21 cells
|
Homo sapiens
|
13.0
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 M4 receptor expressed in BHK-21 cells
|
Homo sapiens
|
72.0
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
|
80.0
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]NMS from human M1 receptor expressed in CHO cells by microplate scintillation counting based radioligand binding assay
|
Homo sapiens
|
7.943
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1).
Year : 2014
Volume : 57
Issue : 21
First Page : 9065
Last Page : 9077
Authors : Bonifazi A, Yano H, Del Bello F, Farande A, Quaglia W, Petrelli R, Matucci R, Nesi M, Vistoli G, Ferré S, Piergentili A.
Abstract : Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.
|
Displacement of [3H]NMS from human M2 receptor expressed in CHO cells by microplate scintillation counting based radioligand binding assay
|
Homo sapiens
|
8.128
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1).
Year : 2014
Volume : 57
Issue : 21
First Page : 9065
Last Page : 9077
Authors : Bonifazi A, Yano H, Del Bello F, Farande A, Quaglia W, Petrelli R, Matucci R, Nesi M, Vistoli G, Ferré S, Piergentili A.
Abstract : Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.
|
Displacement of [3H]NMS from human M3 receptor expressed in CHO cells by microplate scintillation counting based radioligand binding assay
|
Homo sapiens
|
7.762
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1).
Year : 2014
Volume : 57
Issue : 21
First Page : 9065
Last Page : 9077
Authors : Bonifazi A, Yano H, Del Bello F, Farande A, Quaglia W, Petrelli R, Matucci R, Nesi M, Vistoli G, Ferré S, Piergentili A.
Abstract : Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.
|
Displacement of [3H]NMS from human M4 receptor expressed in CHO cells by microplate scintillation counting based radioligand binding assay
|
Homo sapiens
|
11.22
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1).
Year : 2014
Volume : 57
Issue : 21
First Page : 9065
Last Page : 9077
Authors : Bonifazi A, Yano H, Del Bello F, Farande A, Quaglia W, Petrelli R, Matucci R, Nesi M, Vistoli G, Ferré S, Piergentili A.
Abstract : Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.
|
Displacement of [3H]NMS from human M5 receptor expressed in CHO cells by microplate scintillation counting based radioligand binding assay
|
Homo sapiens
|
9.333
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1).
Year : 2014
Volume : 57
Issue : 21
First Page : 9065
Last Page : 9077
Authors : Bonifazi A, Yano H, Del Bello F, Farande A, Quaglia W, Petrelli R, Matucci R, Nesi M, Vistoli G, Ferré S, Piergentili A.
Abstract : Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.
|
Agonist activity at human M1 receptor expressed in HEK293T cells by BRET based Gq protein engagement assay
|
Homo sapiens
|
15.85
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1).
Year : 2014
Volume : 57
Issue : 21
First Page : 9065
Last Page : 9077
Authors : Bonifazi A, Yano H, Del Bello F, Farande A, Quaglia W, Petrelli R, Matucci R, Nesi M, Vistoli G, Ferré S, Piergentili A.
Abstract : Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.
|
Agonist activity at human M1 receptor expressed in HEK293T cells by BRET based Gq protein activation assay
|
Homo sapiens
|
13.18
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1).
Year : 2014
Volume : 57
Issue : 21
First Page : 9065
Last Page : 9077
Authors : Bonifazi A, Yano H, Del Bello F, Farande A, Quaglia W, Petrelli R, Matucci R, Nesi M, Vistoli G, Ferré S, Piergentili A.
Abstract : Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.
|
Agonist activity at human M4 receptor expressed in HEK293T cells by BRET based Gq protein activation assay
|
Homo sapiens
|
16.22
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1).
Year : 2014
Volume : 57
Issue : 21
First Page : 9065
Last Page : 9077
Authors : Bonifazi A, Yano H, Del Bello F, Farande A, Quaglia W, Petrelli R, Matucci R, Nesi M, Vistoli G, Ferré S, Piergentili A.
Abstract : Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.
|
Agonist activity at human M4 receptor expressed in HEK293T cells by BRET based beta-arrestin engagement assay
|
Homo sapiens
|
186.21
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1).
Year : 2014
Volume : 57
Issue : 21
First Page : 9065
Last Page : 9077
Authors : Bonifazi A, Yano H, Del Bello F, Farande A, Quaglia W, Petrelli R, Matucci R, Nesi M, Vistoli G, Ferré S, Piergentili A.
Abstract : Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.
|
Agonist activity at human muscarinic M1 receptor expressed in CHO cells after 30 mins by GTPgamma35S binding assay
|
Homo sapiens
|
67.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M₁ agonists.
Year : 2015
Volume : 25
Issue : 19
First Page : 4158
Last Page : 4163
Authors : Liu B, Croy CH, Hitchcock SA, Allen JR, Rao Z, Evans D, Bures MG, McKinzie DL, Watt ML, Stuart Gregory G, Hansen MM, Hoogestraat PJ, Jamison JA, Okha-Mokube FM, Stratford RE, Turner W, Bymaster F, Felder CC.
Abstract : The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.
|
Agonist activity at human muscarinic M2 receptor expressed in CHO cells after 30 mins by GTPgamma35S binding assay
|
Homo sapiens
|
121.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M₁ agonists.
Year : 2015
Volume : 25
Issue : 19
First Page : 4158
Last Page : 4163
Authors : Liu B, Croy CH, Hitchcock SA, Allen JR, Rao Z, Evans D, Bures MG, McKinzie DL, Watt ML, Stuart Gregory G, Hansen MM, Hoogestraat PJ, Jamison JA, Okha-Mokube FM, Stratford RE, Turner W, Bymaster F, Felder CC.
Abstract : The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.
|
Agonist activity at human muscarinic M4 receptor expressed in CHO cells after 30 mins by GTPgamma35S binding assay
|
Homo sapiens
|
229.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M₁ agonists.
Year : 2015
Volume : 25
Issue : 19
First Page : 4158
Last Page : 4163
Authors : Liu B, Croy CH, Hitchcock SA, Allen JR, Rao Z, Evans D, Bures MG, McKinzie DL, Watt ML, Stuart Gregory G, Hansen MM, Hoogestraat PJ, Jamison JA, Okha-Mokube FM, Stratford RE, Turner W, Bymaster F, Felder CC.
Abstract : The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.
|
Agonist activity at human muscarinic M5 receptor expressed in CHO cells after 30 mins by GTPgamma35S binding assay
|
Homo sapiens
|
142.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M₁ agonists.
Year : 2015
Volume : 25
Issue : 19
First Page : 4158
Last Page : 4163
Authors : Liu B, Croy CH, Hitchcock SA, Allen JR, Rao Z, Evans D, Bures MG, McKinzie DL, Watt ML, Stuart Gregory G, Hansen MM, Hoogestraat PJ, Jamison JA, Okha-Mokube FM, Stratford RE, Turner W, Bymaster F, Felder CC.
Abstract : The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.
|
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
|
269.15
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 CHO cells after 60 mins by scintillation counting assay
|
Homo sapiens
|
316.23
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.
|
Agonist activity at human Muscarinic acetylcholine receptor M4 expressed in HEK cells co-expressing Glosensor construct assessed as decrease in isoproterenol-induced cAMP accumulation incubated for 7 mins in presence of isoproterenol by Glosensor cAMP reagent/plate reader based luminescence assay
|
Homo sapiens
|
18.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of Selective M4 Muscarinic Acetylcholine Receptor Agonists with Novel Carbamate Isosteres.
Year : 2019
Volume : 10
Issue : 6
First Page : 941
Last Page : 948
Authors : Yang Q, Lachapelle EA, Kablaoui NM, Webb D, Popiolek M, Grimwood S, Kozak R, O'Connor RE, Lazzaro JT, Butler CR, Zhang L.
Abstract : It has been hypothesized that selective muscarinic acetylcholine receptor (mAChR) M4 subtype activation could provide therapeutic benefits to a number of neurological disorders while minimizing unwanted cholinergic side effects observed due to nonselective mAChR activation. Given the high sequence and structural homology of the orthosteric binding sites among mAChRs, achieving M4 subtype-selective activation has been challenging. Herein, we describe the discovery of a series of M4 subtype-selective agonists bearing novel carbamate isosteres. Comparison of the isosteres' electrostatic potential isosurface sheds light on key structural features for M4 subtype-selective activation. The identified key features were further illustrated in a proposed receptor-agonist interaction mode.
|
Positive allosteric modulatory activity at human Muscarinic acetylcholine receptor M4 expressed in HEK cells co-expressing Glosensor construct assessed as as increase in acteylcholine-induced cAMP accumulation incubated for 7 mins in presence of isoproterenol/acetylcholine by Glosensor cAMP reagent/plate reader based luminescence assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of Selective M4 Muscarinic Acetylcholine Receptor Agonists with Novel Carbamate Isosteres.
Year : 2019
Volume : 10
Issue : 6
First Page : 941
Last Page : 948
Authors : Yang Q, Lachapelle EA, Kablaoui NM, Webb D, Popiolek M, Grimwood S, Kozak R, O'Connor RE, Lazzaro JT, Butler CR, Zhang L.
Abstract : It has been hypothesized that selective muscarinic acetylcholine receptor (mAChR) M4 subtype activation could provide therapeutic benefits to a number of neurological disorders while minimizing unwanted cholinergic side effects observed due to nonselective mAChR activation. Given the high sequence and structural homology of the orthosteric binding sites among mAChRs, achieving M4 subtype-selective activation has been challenging. Herein, we describe the discovery of a series of M4 subtype-selective agonists bearing novel carbamate isosteres. Comparison of the isosteres' electrostatic potential isosurface sheds light on key structural features for M4 subtype-selective activation. The identified key features were further illustrated in a proposed receptor-agonist interaction mode.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
8.86
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.17
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.17
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
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
|
213.8
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
|
724.44
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
|
380.19
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
|
323.59
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
|
275.42
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 [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
|
Homo sapiens
|
199.53
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.
