Phenyl-substituted analogs of oxotremorine as muscarinic antagonists

• Published in: Journal of medicinal chemistry Vol. 35; no. 2; pp. 285 - 294
• Main Authors: Nilsson, Bjoern M, Vargas, Hugo M, Ringdahl, Bjoern, Hacksell, Uli
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.01.1992; Amer Chemical Soc
• Subjects: Animals; Binding, Competitive; Cerebral Cortex - metabolism; Chemistry; Chemistry, Medicinal; Exact sciences and technology; Guinea Pigs; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; In Vitro Techniques; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Male; Mice; Muscle, Smooth - drug effects; N-Methylscopolamine; Organic chemistry; Oxotremorine - analogs & derivatives; Oxotremorine - antagonists & inhibitors; Oxotremorine - chemical synthesis; Oxotremorine - pharmacology; Parasympatholytics - chemical synthesis; Parasympatholytics - pharmacology; Pharmacology & Pharmacy; Preparations and properties; Rats; Rats, Inbred Strains; Receptors, Muscarinic - drug effects; Science & Technology; Scopolamine Derivatives - metabolism; Structure-Activity Relationship; Tremor - chemically induced; Tremor - prevention & control; GUINEA-PIG ILEUM; REGIONAL DIFFERENCES; GENERAL-SYNTHESIS; POTENTIAL PHARMACOLOGICAL VALUE; AGENT N-METHYL-N-(1-METHYL-4-PYRROLIDINO-2-BUTYNYL)ACETAMIDE; MOLECULAR MODIFICATION; GAMMA-BUTYROLACTONE; N-ACYLAZIRIDINES; RECEPTOR RESERVE; ACETYLENE-COMPOUNDS; Competitive fixation; Five membered ring; Acetylenic compound; Nitrogen heterocycle; Analog; Lactam; Carboxamide; Biological activity; Parasympathomimetic
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00080a013

A series of phenyl-substituted analogues of the muscarinic agent oxotremorine (1) have been prepared. The new compounds (3b-11b and 9c) were assayed for antimuscarinic activity on the isolated guinea pig ileum and in intact mice. They were also evaluated for ability to inhibit the binding of the muscarinic antagonist (-)-[H-3]-N-methylscopolamine to homogenates of the rat cerebral cortex. The phenyl-substituted derivatives were devoid of intrinsic muscarinic activity. Instead, they behaved as competitive muscarinic antagonists in these assays with similar or lower affinity for muscarinic receptors than the corresponding methyl-substituted analogues. The succinimide (8b) and the pyrrolidone (3b) derivatives of 1 substituted with a phenyl group at position 1 of the butynyl chain showed the highest antimuscarinic potency with dissociation constants (K(D)) of 0.10 and 0.20-mu-M, respectively, in the ileum assay. The phenyl-substituted analogues showed an approximately 10-fold lower in vivo antimuscarinic potency than their corresponding methyl-substituted positional isomers. A correlation was observed between in vitro and in vivo potency within subsets consisting of methyl- and phenyl-substituted derivatives.