title: Interaction of azimilide with neurohumoral and channel receptors.
abstract: 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.
authors.affiliation: Procter & Gamble Pharmaceuticals, 11810 E. Miami River Rd., Cincinnati, OH 45252, USA. brooks.rr@pg.com
authors.forename: R R
authors.initials: RR
authors.lastname: Brooks
authors.forename: S F
authors.initials: SF
authors.lastname: Pong
authors.forename: N J
authors.initials: NJ
authors.lastname: Izzo
authors.forename: T J
authors.initials: TJ
authors.lastname: Moorehead
authors.forename: M
authors.initials: M
authors.lastname: Gopalakrishnan
authors.forename: D J
authors.initials: DJ
authors.lastname: Triggle
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D004285:Dogs; D006168:Guinea Pigs; D006827:Hydantoins; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D010879:Piperazines; D011941:Receptors, Adrenergic; D011976:Receptors, Muscarinic; D017981:Receptors, Neurotransmitter; C086123:azimilide; D000254:Sodium-Potassium-Exchanging ATPase