These results indicate that PAF may be involved in the induction of biphasic cutaneous reactions mediated by IgE, and Y-24180 is more effective compared with WEB2086 in this model. It is possible that the difference in the effectiveness between Y-24180 and WEB2086 depends on the persistence of those activities.

The data indicate practical participation of PAF in the development of antigen-induced asthmatic responses in animals, and usefulness of Y-24180 in the clinical treatment of asthma as well as other anti-asthmatic drugs.

No abstract

(±)-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 (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 substitutent 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 (ED₅o: 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.

The effect of Y-24180, a potent antagonist to platelet-activating factor (PAF), was evaluated on the antigen-induced immediate asthmatic response (IAR) in actively sensitized guinea pigs that were pretreated with an antihistaminic agent, pyri-lamine. Then, the effect was compared with that of other antiasthmatic agents. In a dose-dependent manner, Y-24180 (0.01–1 mg/kg, p.o.) suppressed the IAR, and WEB 2086 (0.1–10 mg/kg, p.o.), another PAF antagonist, also suppressed IAR in the same fashion as Y-24180. In contrast, AA-2414 (1–100 mg/kg, p.o.), a thromboxane A2 (TXA2) antagonist, was effective only at the beginning of the IAR and ONO-1078 (1–100 mg/kg, p.o.), a peptide leukotriene (pLT) antagonist, was effective only in the latter period, OKY-046, a TXA₂ synthetase inhibitor, showed no significant suppression of the IAR at doses up to 100 mg/kg. Thus, PAF antagonists were more effective than the other agents tested in the present model for IAR. In a subsequent test, Y-24180 (1 mg/kg, p.o.) was confirmed to enhance the suppressive effects of theophylline (10 and 30 mg/kg, p.o.), procaterol (0.1 and 1 µg/kg, i.v.), OKY-046 (100 mg/kg, p.o.) and ONO-1078 (100 mg/kg, p.o.) on the IAR. A combination of three agents, namely Y-24180 with OKY-046 and ONO-1078, completely suppressed the IAR. The results demonstrate that Y-24180 not only suppresses the IAR, but also enhances the suppressive effect of other antiasthmatic agents. Therefore, Y-24180 would be a clinically promising drug for the treatment of bronchial asthma.