title: ICI 169,369 is both a competitive antagonist and an allosteric activator of the arterial 5-hydroxytryptamine2 receptor system.
abstract: The mode of action of ICI 169,369, a novel 5-hydroxytryptamine2 (5-HT2) receptor antagonist, was investigated in arterial muscle. Isolated preparations from calf coronary artery and from rat tail artery with the endothelium rubbed off were set up to contract isometrically with 5-HT. ICI 169,369 (1-3000 nM) antagonized surmountably and competitively the contractile effects of 5-HT in coronary artery (pKB, 9.1) and tail artery (pKB, 8.8). Methysergide antagonized unsurmountably 5-HT-induced contractions by reducing maximum effects to 25% (coronary artery: pIC50, 9.8) and 60% (tail artery: pIC80, 9.0). ICI 169,369 (100-300 nM) restored the maximum effects of 5-HT that had been depressed by methysergide (20 nM coronary artery, 100 nM tail artery). Preincubation with ICI 169,369 also prevented the methysergide-induced depression of the maximum effects of 5-HT. The protective effect of ICI 169,369 was overcome by high methysergide concentrations (up to 3 microM), suggesting competition between the two drugs for a common site. The data are consistent with an allosterically modulated interconversion of the 5-HT2 receptor between two states (R in equilibrium R'). ICI 169,369 competes with 5-HT for the 5-HT2 receptor. ICI 169,369 and methysergide also compete for an allosteric site of the 5-HT2 receptor system, thereby facilitating the highly active R-state and low active R'-state, respectively.
authors.affiliation: ICI Pharmaceutical Division, Cheshire, United Kingdom.
authors.forename: A J
authors.initials: AJ
authors.lastname: Kaumann
authors.forename: M
authors.initials: M
authors.lastname: Frenken
mesh_terms: D000495:Allosteric Site; D000818:Animals; D001158:Arteries / Q000187:drug effects; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008784:Methysergide / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D011804:Quinolines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C054363:2-((2-(dimethylamino)ethyl)thio)-3-phenylquinoline; D008784:Methysergide