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.