Structural Requirements for Muscarinic Receptor Occupation and Receptor Activation by Oxotremorine Analogs in the Guinea-Pig lleum1

The muscarintc activities in the isolated guinea-pig ileum of nine analogs of oxotremorine, modified only in the amino group, were resolved into affinity and efficacy components. The method used involved analysis of dose-response data before and after frac-tional inactivation of receptors with propylbenzilylcholine mus-tard. The dissodation constants (1(4 thus Obtned for oxotre-morine (6.79 x i0 M), oxotremonne methiodide (6.74 x i0 M) and oxotremorine-M (2.92 x i0 M) agreed well with their reported low-affinity dissociation constants (KU determined in receptor binding studies. There was no correlation between relative affinities and efficacies of the nine agonists studied, suggesting different structural requirements for occupation and acthiaon of muscatinic receptors in the guinea-prn ileum. Al-though oxotremo#{231}pnehad higher affinfty than its analogs, some of the latter had substantially greater efficacy than oxotremorine