Dronedarone Modulates M₁ and M₃ Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence

Abstract

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.

Is Low Heart Rate Variability Associated with Emotional Dysregulation, Psychopathological Dimensions, and Prefrontal Dysfunctions? An Integrative View

“…Given the importance of HRV on a whole series of parameters and variables, it has been shown how antiarrhythmic agents alter HRV with a direct effect on the ANS and myocardial contractility. Different comparative analyses showed that Amiodarone, despite interacting with the ANS centrally [ 49 ] and peripherally [ 50 , 51 ] did not affect HRV. On the other hand, Flecainide and Propafenone have vagolytic [ 52 ] and beta-blocking [ 53 ] properties, which could further modulate sympathetic and parasympathetic activity in the heart [ 54 , 55 ] decreasing all the parameters of HRV in the time domain and the frequency domain including the markers of vagal activity [ 56 ].…”

Hybrid Allosteric Modulators of M1 Muscarinic Receptors Enhance Acetylcholine Efficacy and Decrease Locomotor Activity and Turning Behaviors in Zebrafish

“…Amiodarone is best known as an antiarrhythmic agent that blocks potassium channels, but it has also been shown to enhance muscarinic receptor activity through an allosteric mechanism. [24][25][26] Initial studies con rmed that amiodarone is a PAM of ACh at M 1 receptors, based on measurements of [ 3 H]-AA release in stably transfected CHO cells (Fig. 2; Table 1).…”

“… 24 A similar phenomenon has been observed at the M 1 and M 5 muscarinic subtypes. 25 , 26 We are not aware of any other PAM of a G protein-coupled receptor that increases the maximal response of the endogenous ligand without enhancing its potency.…”

“…Compounds also were tested in vivo to assess preliminary toxicology and effects on locomotor behaviors in zebrafish ( Danio rerio ). Based on the structures of BQCA/VU0119498 (potency modulators) and amiodarone/dronedarone (efficacy modulators), 25 we hypothesized that a hybrid compound could result in useful additive effects (i.e., potency and efficacy modulation, Fig. 1 ).…”

Cholinergic System and Its Therapeutic Importance in Inflammation and Autoimmunity

“…It shows a therapeutic efficacy for treating Alzheimer's disease, Huntington's disease, and schizophrenia in the animal model (192)(193). Amiodarone Gq-mediated responses are positively modulated at M 1 mAChR and M 3 mAChR but inhibited in a more discriminating fashion at the M 1 mAChR (194,195).…”