Structural requirements for affinity and efficacy of N-(4-amino-2-butynyl)succinimides at muscarinic receptors in the guinea-pig ileum and urinary bladder

Abstract

The muscarinic activities on the isolated guinea-pig ileum and urinary bladder of some N-(4-amino-2-butynyl)succinimides, modified only in the amino group, were resolved into receptor affinity and efficacy components. The structural requirements for high affinity and high efficacy were quite different. Cyclic tertiary amino moieties generally favoured high affinity, while small acyclic amino and ammonium groups favoured high efficacy. On the ileum, dissociation constants and relative efficacies of the succinimides were highly correlated (r = 0.94-0.97) with those of the identically modified N-(4-amino-2-butynyl)-2-pyrrolidones. This observation suggests that N-(4-amino-2-butynyl)succinimides and 2-pyrrolidones bind to and activate muscarinic receptors in a similar fashion. In spite of their agonist properties on the ileum, the succinimides studied were agonists, partial agonists or competitive antagonists on the urinary bladder. However, dissociation constants and relative efficacies of the compounds showed good agreement in the two tissues. It therefore appears that muscarinic receptors in the guinea-pig ileum and urinary bladder are pharmacologically similar. The large differences observed in agonist potency and relative maximal responses between the two tissues were explained by a greater receptor reserve for muscarinic agonists in the ileum than in the bladder.