title: Effect of Y-24180, a long-acting antagonist to platelet-activating factor (PAF), on PAF-induced reactions: a relationship between the partial structure of the compound and its duration of the action.
abstract: (+/-)-4-(2-Chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dime thy l-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (Y-24180) is a platelet-activating factor (PAF) antagonist, being similar to WEB 2086. One of the structural differences between the two PAF antagonists is the presence of a methyl substituent in Y-24180 at the 6-position of its ring system. Orally administered Y-24180 and WEB 2086 both dose-dependently prevented PAF-induced airway hyperresponsiveness (ED50: 0.0010 and 0.019 mg/ kg, respectively) and bronchoconstriction (ED50: 0.0014 and 0.024 mg/kg, respectively) in guinea pigs. Against the bronchoconstriction, here, the inhibitory effect of Y-24180 was significantly more potent and longer acting than that of WEB 2086. On the other hand, Y-24180 (10 mg/kg, p.o.) showed insignificant effects on the bronchoconstriction induced by leukotriene D4, histamine, serotonin, acetylcholine, arachidonic acid, or bradykinin. In an in vitro test, Y-24180 and WEB 2086 inhibited the PAF-induced aggregation of the rabbit washed platelets in a concentration-dependent manner (IC50: 1.2 and 64 nmol/l, respectively). Compared with desmethyl-Y-24180 and WEB 2086, Y-24180 and methyl-WEB 2086, both of which have a methyl substituent on the 6-position of their thienodiazepine ring, exhibited a longer acting suppressive effect on PAF-induced bronchoconstriction and significantly more stable binding to the PAF receptor after the washing-out procedure of the test compounds from platelets. Therefore, the 6-methyl substituent should be responsible for the PAF receptor binding stability of Y-24180, namely, for its long-acting anti-PAF effects in vivo. These results indicate that Y-24180 possesses the specific and long-acting PAF antagonistic effects in the airway.
authors.affiliation: Research Laboratories, Yoshitomi Pharmaceutical Industries Ltd, Fukuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kagoshima
authors.forename: N
authors.initials: N
authors.lastname: Tomomatsu
authors.forename: Y
authors.initials: Y
authors.lastname: Iwahisa
authors.forename: S
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Kawakami
authors.forename: M
authors.initials: M
authors.lastname: Terasawa
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D001920:Bradykinin / Q000008:administration & dosage / Q000633:toxicity; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000517:prevention & control*; D016084:Bronchoconstriction / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006632:Histamine / Q000008:administration & dosage / Q000633:toxicity; D007275:Injections, Intravenous; D017998:Leukotriene D4 / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000633:toxicity; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011817:Rabbits; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012701:Serotonin / Q000008:administration & dosage / Q000633:toxicity; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001381:Azepines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086; 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; D012701:Serotonin; D017998:Leukotriene D4; D006632:Histamine; D000109:Acetylcholine; D001920:Bradykinin