Pharmacological analysis of the mode of interaction of McN-A-343 at atrial muscarinic M2 receptors

The mode of interaction of the muscarinic M-2 receptor partial agonist, McN-A-343 (4-(m-chlorophenylcarbamoyloxy)-2-butynyltri methylammonium), was investigated in the electrically-driven guinea-pig left atrium. Comparison of the negative inotropic responses to this agent with those of the full agonist, carbachol, followed by operational model-fitting, yielded estimates of the dissociation constant (K-A) and efficacy (tau) of McN-A-343. Following partial receptor inactivation with propylbenzylcholine mustard, the properties of McN-A-343 as an inhibitor of the carbachol-mediated responses were assessed. Analysis of the data, according to both competitive and allosteric models of interaction, favored the former model. The log K-B of McN-A-343 as an antagonist was -4.65 +/- 0.06, and was not significantly different from the log K-A of this agent as an agonist. (C) 1997 Elsevier Science B.V.