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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Bibliographische Detailangaben
Veröffentlicht in:	Bioorganic & medicinal chemistry letters 1999-07, Vol.9 (14), p.1895-1900
Hauptverfasser:	SABB, A. L, HUSBANDS, G. M, TOKOLICS, J, STEIN, R. P, TASSE, R. P, BOAST, C. A, MOYER, J. A, ABOU-GHARBIA, M
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Biological and medical sciences Bridged-Ring Compounds - chemistry Bridged-Ring Compounds - pharmacology Carbachol - chemistry Carbachol - metabolism Carbachol - pharmacology Cerebral Cortex - metabolism CHO Cells - metabolism Cholinergic system Cognition Disorders - drug therapy Computer Simulation Cricetinae Crystallography, X-Ray Drug Design Drug Evaluation, Preclinical Humans Macaca mulatta Maze Learning - drug effects Medical sciences Models, Molecular Muscarinic Agonists - chemistry Muscarinic Agonists - pharmacology Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Phosphatidylinositols - metabolism Protein Conformation Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Pyrazines - chemistry Pyrazines - pharmacology Pyridines - chemistry Pyridines - pharmacology Rats Receptor, Muscarinic M1 Receptors, Muscarinic - chemistry Receptors, Muscarinic - metabolism Salivation - drug effects Structure-Activity Relationship Thiadiazoles - chemistry Thiadiazoles - pharmacology
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Beschreibung
Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/S0960-894X(99)00313-3