Interaction of azimilide with neurohumoral and channel receptors

Binding of the class III antiarrhythmic agent azimilide to brain, heart, an d other organ receptors was assessed by standard radioligand binding techni ques. In a survey of 60 receptors, azimilide at 10 muM inhibited binding by more than 50% at serotonin uptake (K-i: 0.6 muM), muscarinic (K-i: 0.9 to -3.0 muM), Na+ channel site 2 (K-i: 4.3 muM), and central sigma (K-i: 6.2 m uM) sites. Lesser (20-40%) inhibition was seen at adrenergic, histamine, se rotonin, purinergic, angiotensin II, dopamine uptake, and norepinephrine si tes and at a voltage-sensitive K+ channel. In rat ventricle, azimilide inhi bited binding to alpha (1)- and beta -adrenergic and muscarinic receptors ( K-i: <5 muM) and to the L-type Ca2+ channel (K-i: 37.3 muM). In rat brain, azimilide blocked ligand binding to these same receptors and to a serotonin receptor, and the breadth and potency of its interaction pattern different iated it from ten other class HI antiarrhythmics. Azimilide displayed agoni st and antagonist action at five muscarinic. receptor subtypes in transfect ed. NIH 3T3 cells producing receptor-sensitive mitogenesis and beta -galact osidase activity. Agonist action predominated at M-2 and M-4 subtypes, and antagonist action predominated at M-1 M-3 and M-5 subtypes. The azimilide c oncentration for 50% maximum stimulation (EC50) in M-2-expressing cells was 1.97 muM (vs 0.14 muM for carbachol). Azimilide's receptor interactions oc cur at concentrations from one to forty times those required to block cardi ac delayed-rectifier channels but could contribute to the efficacy and safe ty of the drug. (C) 2001 Elsevier Science Inc. All rights reserved.