Muscarinic orthosteric site modulators that have excellent affinity for muscarinic receptors are usually without high receptor subtype selectivity, which is necessary to reduce muscarinic side effects and has limited their usefulness as therapeutics. Stahl and Ellis investigated the binding of the antiarrhythmic drug amiodarone to muscarinic receptors and demonstrate a novel allosteric interaction of amiodarone with the M1 and M5 receptors. Amiodarone does not interact at the “common” obidoxime binding site, and [3H]N-methylscopalamine (NMS) was able to bind simultaneously with amiodarone, suggesting a novel allosteric mode of binding that alters the rate of NMS dissociation from M1 and M5 receptors. Functionally, amiodarone allosterically enhanced the efficacy but not the potency of acetylcholine at the M5 receptor; however, amiodarone did not enhance M1 receptor activation. These results are the first to demonstrate an allosteric enhancement of efficacy but not potency at any muscarinic receptor and that amiodarone is a novel M5-selective positive allosteric modulator of muscarinic receptors.
See article at J Pharmacol Exp Ther 2010, 334:214–222.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics