Amiodarone and N‐ethyl‐amiodarone exert opposing allosteric effects via a novel site on muscarinic receptors

Abstract

Allosteric modulation provides several advantages over the classical (orthosteric) approach to receptor activation; further, the characterization of new allosteric sites provides additional opportunities for the development of subtype‐selective and functionally selective compounds. We have been investigating the allosteric actions of amiodarone and N‐ethyl‐amiodarone (NEA) at muscarinic receptors. Previous studies have demonstrated that amiodarone interacts with a site that is distinct from the one that has been defined by gallamine.We have shown that amiodarone enhances stimulation of [3H]arachidonic acid release induced by agonists acting at Gq‐coupled muscarinic receptors. Evaluation of this action in light of Hall's allosteric two‐state model indicates that amiodarone's enhancement of agonist efficacy is tempered by a concomitant reduction in agonist binding affinity. The enhancement of efficacy is attenuated by NEA but not by the orthosteric antagonist N‐methylscopolamine; further evaluation of this finding using an elaboration of Hall's model suggests that amiodarone and NEA exert their functional effects through a common allosteric site.In conclusion, we have demonstrated that amiodarone and NEA interact allosterically with a novel, extracellular, site on muscarinic receptors, through which they modulate agonist potency and efficacy in a complex manner.