Affinity, efficacy, and stereoselectivity of oxotremorine analogues for muscarinic receptors in the isolated guinea pig ileum

• Published in: Molecular pharmacology Vol. 23; no. 1; pp. 17 - 25
• Main Authors: Ringdahl, B, Jenden, D J
• Format: Journal Article
• Language: English
• Published: United States 01.01.1983
• Subjects: acetylcholine; Animals; Atropine - metabolism; Carbachol - metabolism; Dibenzylchlorethamine - metabolism; Dose-Response Relationship, Drug; Guinea Pigs; Hexamethonium; Hexamethonium Compounds - metabolism; ileum; Ileum - metabolism; Isomerism; Male; oxotremorine; Oxotremorine - analogs & derivatives; Oxotremorine - metabolism; Parasympatholytics - metabolism; Receptors, Cholinergic - metabolism; Receptors, Muscarinic - metabolism; Structure-Activity Relationship
• ISSN: 0026-895X

The seven possible tertiary structural isomers obtained by the introduction of a single methyl group in the muscarinic agent oxotremorine (N-(4-pyrrolidino-2-butynyl)-2-pyrrolidone), and some related compounds, were investigated for muscarinic and antimuscarinic activity in the isolated guinea pig ileum. The structural requirements for achieving high affinity appear to be independent of those leading to high efficacy. Some compounds showed a pronounced stereoselectivity of action, whereas others exhibited little or no stereoselectivity. The degree of stereoselectivity is well correlated with the affinity of the more potent member of each enantiomeric pair. A good correlation was observed between parasympatholytic potency in vitro and previously reported tremorolytic potencies in mice of 24 structurally related oxotremorine analogues.