Muscarinic and antimuscarinic activity of acetamides related to oxotremorine in the guinea pig urinary bladder

B Ringdahl and ME Markowicz

Eight acetamide analogs of oxotremorine, shown previously to be full or nearly full muscarinic agonists on the isolated guinea pig ileum, were investigated for muscarinic activity on muscle strips of guinea pig urinary bladder. Several compounds demonstrated pronounced organ selectivity when compared to carbachol by being partial agonists or antagonists on the bladder. For example, oxotremorine and BM 34, both potent, full agonists on the ileum, were partial agonists, the latter producing less than one-half the maximum response of carbachol. BM 5 elicited no significant response, but instead was a potent antagonist to carbachol. Schild analysis with BM 5 and BM 61 indicated no muscarinic receptor heterogeneity between the bladder and ileum. Also dissociation constants of agonists and partial agonists generally agreed with those determined previously on the ileum. Furthermore, the relative efficacy of each agonist appeared to be similar in the two tissues, confirming the homogeneity of muscarinic receptors in the bladder and ileum with respect to the compounds studied. Compounds having high affinity and low intrinsic efficacy, e.g., BM 5, thus may stimulate contractile responses on the ileum and block responses on the bladder and therefore display tissue selectivity without discriminating between tissue receptors. It is suggested that this selectivity is derived from a smaller effective receptor reserve for muscarinic agonists in the bladder.

Volume 240, Issue 3, pp. 789-794, 03/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics