Binding profiles of class I antiarrhythmic agents to cardiac muscarinic receptors: competitive and allosteric interactions with the receptors and their pharmacological significance.

The binding profiles of the class I antiarrhythmic agents disopyramide, pirmenol and pentisomide (CM7857) to cardiac muscarinic receptors were characterized by the binding assay using [3H]-N-methyl scopolamine ([3H]NMS) as a ligand and their anti-muscarinic actions were investigated functionally in left atrial preparations. All the agents displaced the specific binding of 200 pM [3H]NMS from guinea pig left atrial membranes. Computer-assisted analysis indicated that pirmenol interacted with a single class of binding sites, but the displacement curves of disopyramide and pentisomide were shallow and best fitted to a two-site model. When the concentration of [3H]NMS was increased to 1 nM, the displacement curve of pirmenol was best fitted to a two-site model. In higher concentrations, these agents inhibited the dissociation of [3H]NMS initiated by 1 microM atropine in a concentration-dependent manner, thus revealing allosteric interactions. Two enantiomers of pirmenol possessed qualitatively the same binding properties as the racemate. In guinea pig left atria, disopyramide, pirmenol and pentisomide shifted the concentration-response curves for the negative inotropic effect of carbachol in a parallel manner. The slopes of Schild plot were not significantly different from unity, indicating that they act as a competitive antagonist of cardiac muscarinic receptors. Excellent correlation between the high affinity pKi values and the pA2 values was established for the antiarrhythmic agents. These findings suggest that disopyramide, pirmenol and pentisomide all interact with cardiac muscarinic receptors in both a competitive fashion and an allosteric one. The dual mode of the interaction with cardiac muscarinic receptors seems to be independent of their chiralities.(ABSTRACT TRUNCATED AT 250 WORDS)