We have previously reported that amiodarone interacts with a novel allosteric site on muscarinic receptors. Amiodarone's most striking effect is to enhance the maximal response elicited by muscarinic agonists at the M1, M3, and M5 receptors. Furthermore, the quaternary analog N-ethylamiodarone (NEA) is inhibitory at these receptors and appears to compete with amiodarone at that allosteric site. In the present studies, we show that dronedarone also modulates Gq-mediated responses at M1 and M3, although in a more discriminating manner. For example, dronedarone markedly enhances pilocarpine-stimulated release of arachidonic acid from CHO cells, via the M3 receptor subtype, but does not affect the acetylcholine-stimulated response. Such probe-dependent effects are diagnostic of an allosteric interaction. In comparison to these effects at M3, dronedarone is strongly inhibitory toward both pilocarpine and acetylcholine at the M1 subtype. The effects of dronedarone are consistent with an interaction at the amiodarone site: dronedarone inhibits the enhancement of acetylcholine's response produced by amiodarone at the M3 subtype; also, NEA reverses the enhancement of pilocarpine's response at M3 produced by either dronedarone or amiodarone. In studies with the M1-selective allosteric agonist 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC-260584), amiodarone enhanced the maximal response observed, whereas dronedarone was inhibitory. On the other hand, benzyl quinolone carboxylic acid, the well-known allosteric ligand that dramatically enhances the potency of acetylcholine at the M1 subtype, had no effect on the response profile of AC-260584. In summary, dronedarone acts at M1 and M3 muscarinic receptors in a manner that complements amiodarone and provides an additional tool with which to investigate this novel allosteric site.
We have previously reported that amiodarone interacts with a novel allosteric site on muscarinic receptors. Amiodarone’s most striking effect is to enhance the maximal response elicited by muscarinic agonists at the M1, M3, and M5 receptors. Furthermore, the quaternary analog N‐ethylamiodarone (NEA) is inhibitory at these receptors and appears to compete with amiodarone at that allosteric site. In the present studies, we show that dronedarone (DRON) also modulates Gq‐mediated responses, although in a more discriminating manner. For example, DRON markedly enhances pilocarpine‐stimulated release of arachidonic acid from CHO cells, via the M3 receptor subtype, but does not affect the acetylcholine‐stimulated response. In comparison to these effects at M3, DRON is strongly inhibitory toward both pilocarpine and acetylcholine at the M1 subtype. The effects of DRON are consistent with an interaction at the amiodarone site: DRON inhibits the enhancement of acetylcholine’s response produced by amiodarone at the M3 subtype; and, NEA reverses the enhancement of pilocarpine’s response at M3 produced by either DRON or amiodarone. In studies with the M1‐selective allosteric agonist AC260584, amiodarone enhanced the maximal response observed, whereas DRON was inhibitory. On the other hand, BQCA, the well‐known PAM that dramatically enhances the potency of acetylcholine at the M1 subtype, had no effect on the response profile of AC260584. In summary, DRON acts at Gq‐linked muscarinic receptors in a manner that complements amiodarone and provides an additional tool with which to investigate this novel allosteric site. Grant Funding Source: Supported by PHS R01 005214 to JE
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.