title: Pharmacological actions of Y-24180: I. A potent and specific antagonist of platelet-activating factor.
abstract: The ability of Y-24180, 4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]- 6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepine to inhibit platelet-activating factor (PAF)-induced reactions was investigated. Y-24180 (0.0003-0.003 mg/kg, i.v.) dose-dependently inhibited PAF-induced bronchoconstriction in guinea pigs, but even at a high dose of 10 mg/kg, i.v., it was either inactive or weakly active against the bronchoconstriction induced by histamine, serotonin, acetylcholine, arachidonic acid, bradykinin, or leukotriene D4. Oral doses (0.003-0.1 mg/kg) of Y-24180 also prevented hemoconcentration due to PAF in a dose dependent manner and produced a parallel shift of the PAF dose-response curve. Y-24180 (0.0003-0.1 mg/kg, i.v.) and WEB 2086 (0.03-1 mg/kg, i.v.) dose-dependently reversed PAF-induced hypotension in anesthetized rats. In mice, PAF-induced lethality was inhibited by Y-24180 and WEB 2086 with ED50 values of 0.022 and 1.42 mg/kg, p.o., and 0.023 and 0.12 mg/kg, i.v., respectively. This protective effect of Y-24180 given p.o. persisted for at least 6 hr. In actively sensitized mice lethal anaphylactic shock was prevented by oral doses of Y-24180 and WEB 2086 with ED50 values of 0.095 and 0.69 mg/kg, respectively. These results suggested that Y-24180 is an extremely potent and specific PAF antagonist with a good duration of action.
authors.affiliation: Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Fukuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Terasawa
authors.forename: H
authors.initials: H
authors.lastname: Aratani
authors.forename: M
authors.initials: M
authors.lastname: Setoguchi
authors.forename: T
authors.initials: T
authors.lastname: Tahara
mesh_terms: D000707:Anaphylaxis / Q000517:prevention & control; D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001980:Bronchi / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D006400:Hematocrit; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D011917:Rats, Inbred Lew; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C068035:4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-6,9-dimethyl-6H-thieno(3,2-f)(1,2,4)triazolo(4,3-a)(1,4)diazepine