Interaction of azimilide with neurohumoral and channel receptors

Binding of the class III antiarrhythmic agent azimilide to brain, heart, and other organ receptors was assessed by standard radioligand binding techniques. In a survey of 60 receptors, azimilide at 10 μM inhibited binding by more than 50% at serotonin uptake (K_i: 0.6 μM), muscarinic (K_i: 0.9 to -3.0 μM), Na⁺ channel site 2 (K_i: 4.3 μM), and central sigma (K_i: 6.2 μM) sites. Lesser (20-40%) inhibition was seen at adrenergic, histamine, serotonin, purinergic, angiotensin II, dopamine uptake, and norepinephrine sites and at a voltage-sensitive K⁺ channel. In rat ventricle, azimilide inhibited binding to α₁- and β-adrenergic and muscarinic receptors (K_i: <5 μM) and to the L-type Ca²⁺ channel (K_i: 37.3 μM). 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 differentiated it from ten other class III antiarrhythmics. Azimilide displayed agonist and antagonist action at five muscarinic receptor subtypes in transfected NIH 3T3 cells producing receptor-sensitive mitogenesis and β-galactosidase activity. Agonist action predominated at M₂ and M₄ subtypes, and antagonist action predominated at M₁, M₃, and M₅ subtypes. The azimilide concentration for 50% maximum stimulation (EC₅₀) in M₂-expressing cells was 1.97 μM (vs 0.14 μM for carbachol). Azimilide's receptor interactions occur at concentrations from one to forty times those required to block cardiac delayed-rectifier channels but could contribute to the efficacy and safety of the drug.