Phenyl-Substituted Analogues of Oxotremorine as Muscarinic Antagonists

Article abstract of 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 (-)-<(3)H>-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 bytynyl chain showed the highest antimuscarinic potency with dissociation constants (K_D) of 0.10 and 0.20 μM, respectively, in the ileum assay.The phenyl-substituted analogues showed an approximately 10-fold lower in vivo antimuscarinic potency than their corresponding methyl-substituted position isomers.A correlation was observed between in vitro and in vivo potency within subsets consisting of methyl- and phenyl-substituted derivatives.