Discovery of a highly potent, functionally-selective muscarinic M1 agonist, WAY-132983 using rational drug design and receptor modelling.
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.
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Wyeth-Ayerst Research, Princeton, NJ 08543-8000, USA.
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D000284:Administration, Oral; D000818:Animals; D001952:Bridged-Ring Compounds / Q000737:chemistry* / Q000494:pharmacology*; D016466:CHO Cells / Q000378:metabolism; D002217:Carbachol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy; D003198:Computer Simulation; D006224:Cricetinae; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008253:Macaca mulatta; D018782:Maze Learning / Q000187:drug effects; D008958:Models, Molecular; D018721:Muscarinic Agonists / Q000737:chemistry* / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011487:Protein Conformation; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000378:metabolism*; D012472:Salivation / Q000187:drug effects; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology
D001952:Bridged-Ring Compounds; D018721:Muscarinic Agonists; D010716:Phosphatidylinositols; D011719:Pyrazines; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; C121282:WAY 132983; D002217:Carbachol; C075257:xanomeline