title: Pharmacological actions of Y-24180, a new specific antagonist of platelet activating factor (PAF): II. Interactions with PAF and benzodiazepine receptors.
abstract: The inhibitory effect of Y-24180, 4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H-t hieno [3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepine, on platelet activating factor (PAF)-induced platelet aggregation and the specific binding of 3H-PAF to platelets was compared with other thienodiazepine derivatives, WEB 2086 and etizolam. Y-24180 inhibited PAF-induced rabbit platelet aggregation in vitro (IC50 3.84 nM), but had little effect on adenosine diphosphate- or arachidonic acid-induced aggregation. WEB 2086 and etizolam also showed an inhibitory effect of PAF-induced aggregation (IC50 values are 456 and 6730 nM, respectively). In PAF-induced human platelet aggregation, Y-24180 (IC50 0.84 nM) was more potent than WEB 2086 (IC50 4.21 nM) and etizolam (IC50 998 nM). Y-24180, WEB 2086 and etizolam displaced 3H-PAF binding from the washed-platelets of rabbits with an IC50 value of 3.50, 9.35 and 29.5 nM, respectively. In rabbits, pretreatment with Y-24180 and WEB 2086 antagonized PAF-induced platelet aggregation dose-dependently. The significant inhibitory effect of Y-24180 (1 mg/kg, p.o.) lasted 72 hr after a single dose oral administration. WEB 2086 (10 mg/kg, p.o.) also antagonized the ex vivo response induced by PAF 1 hr after administration, but no significant effect was observed 3 hr after administration. Y-24180 displaced 3H-diazepam binding from the synaptosomal membranes of rat cerebral cortex with a Ki value of 3.68 microM. The affinity of Y-24180 for benzodiazepine(BZP) receptors was lower than those of WEB 2086 and etizolam and was about 1000 times lower than that for PAF receptors in platelets.
authors.affiliation: Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Fukuoka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Takehara
authors.forename: H
authors.initials: H
authors.lastname: Mikashima
authors.forename: Y
authors.initials: Y
authors.lastname: Muramoto
authors.forename: M
authors.initials: M
authors.lastname: Terasawa
authors.forename: M
authors.initials: M
authors.lastname: Setoguchi
authors.forename: T
authors.initials: T
authors.lastname: Tahara
mesh_terms: D000818:Animals; D001381:Azepines / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D001792:Blood Platelets / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D003975:Diazepam / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins; D011817:Rabbits; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A / Q000378:metabolism; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology*
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; D011963:Receptors, GABA-A; 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; C044610:etizolam; D003975:Diazepam