Interaction of azimilide with neurohumoral and channel receptors

• Published in: Biochemical pharmacology Vol. 62; no. 7; pp. 883 - 892
• Main Authors: BROOKS, Robert R, SCHWE FANG PONG, IZZO, Nicholas J, MOOREHEAD, Thomas J, GOPALAKRISHNAN, Murali, TRIGGLE, David J
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Science 01.10.2001
• Subjects: Animals; Anti-Arrhythmia Agents - pharmacology; Antiarythmic agents; Binding Sites; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Cardiovascular system; Cattle; Dogs; Guinea Pigs; Hydantoins; Imidazoles - pharmacology; Imidazolidines; Kidney - drug effects; Kidney - metabolism; Medical sciences; Mice; Muscarinic Agonists - pharmacology; Muscarinic Antagonists - pharmacology; Pharmacology. Drug treatments; Piperazines - pharmacology; Rabbits; Rats; Receptors, Adrenergic - drug effects; Receptors, Adrenergic - metabolism; Receptors, Muscarinic - drug effects; Receptors, Muscarinic - metabolism; Receptors, Neurotransmitter - drug effects; Receptors, Neurotransmitter - metabolism; Sodium-Potassium-Exchanging ATPase - metabolism; Heart; Agonist; Potassium Cations; Rat; Serotonin; Ligand; Rodentia; Central nervous system; Molecular interaction; Ionic channel; Antiarrhythmic agent; Catecholamine; Cholinergic receptor; Vertebrata; Azimilide; Biological fixation; Mammalia; Animal; Neurotransmitter; Muscarinic receptor; Antagonist; Circulatory system; Adrenergic receptor; Brain (vertebrata)
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(01)00737-7

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 microM inhibited binding by more than 50% at serotonin uptake (K(i): 0.6 microM), muscarinic (K(i): 0.9 to -3.0 microM), Na(+) channel site 2 (K(i): 4.3 microM), and central sigma (K(i): 6.2 microM) 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 alpha(1)- and beta-adrenergic and muscarinic receptors (K(i): < 5 microM) and to the L-type Ca(2+) channel (K(i): 37.3 microM). 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 beta-galactosidase 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 concentration for 50% maximum stimulation (EC(50)) in M(2)-expressing cells was 1.97 microM (vs 0.14 microM 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.