Platelet-activating factor-induced functional changes in the guinea pig trachea in vitro

Tomo, Inoue; Kannan, Mathur

doi:10.1016/0034-5687(89)90003-0

Cited by 3 publications

(1 citation statement)

References 15 publications

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“…Thus, PAF is involved in the pathogenesis of allergic and inflammatory reactions [1]. Especially, PAF relates closely to the pathogenesis of asthma because this mediator causes airway hyperresponsiveness [2][3][4][5], acute bronchoconstriction [6-9], airway microvascular leak age [10][11][12][13], chemotaxis of eosinophils into the lung [14][15][16][17], and so on. These symptoms are prominent pathological features of asthma [18].…”

Section: Introductionmentioning

confidence: 99%

Effect of Y-24180, a Long-Acting Antagonist to Platelet-Activating Factor (PAF), on PAF-lnduced Reactions: A Relationship between the Partial Structure of the Compound and Its Duration of the Action

Kagoshima¹,

Tomomatsu²,

Iwahisa³

et al. 1997

Pharmacology

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(±)-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.

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