ABSTRACT-We evaluated the antagonist activity of ONO-1078 against peptide leukotrienes (LTs) by a radioligand binding assay and functional experiments in guinea pigs. In the radioligand binding assay, ONO-1078 inhibited [3H]LTD4 and [3H]LTE4 bindings to lung membranes (K; = 0.99 and 0.63 nM, re spectively) and was 2,000 to 3,000-fold more potent than FPL55712. Antagonism of ONO-1078 against [3H]LTC4 binding (K; = 5640 nM) was approximately twofold more potent than that of FPL55712. The antagonism of ONO-1078 against [3H]LTD4 binding was competitive. In functional experiments, ONO 1078 showed competitive antagonism against the LTC4 and LTD4-induced contractions of guinea pig trachea and lung parenchymal strips with a pA2 range of 7.70 to 10.71 and was approximately 400 to 3,300-fold more potent than FPL55712. Interestingly, in the presence of an inhibitor of the bioconver sion of LTC4 to LTD4, ONO-1078 also antagonized the LTC4-induced contraction of guinea pig trachea (pA2 = 7.78). ONO-1078 significantly reversed the LTD4-induced prolonged contraction without effect on the KCl and BaC12-induced contractions of guinea pig trachea. Furthermore, ONO-1078 antago nized the antigen-induced SRS-A mediated contraction of guinea pig trachea. On the other hand, ONO-1078 showed no antagonism against histamine, acetylcholine, 5-hydroxytryptamine, prostaglandin D2 and U-46619. In addition, ONO-1078 showed little or no effect on the activities of cyclooxygenase, 5-lipoxygenase and thromboxane synthetase. These in vitro studies indicate that ONO-1078 is a highly potent, selective and competitive antagonist of peptide leukotrienes that acts with higher affinity at LTD4 and LTE4 receptors than LTC4 receptors.

ABSTRACT-We investigated the in vivo antagonistic activity of ONO-1078 against peptide leuko trienes (LTs) in guinea pigs. ONO-1078, when administered p.o. (0.3-3 mg/kg), caused a dose-depend ent reduction of LTC4-, LTD4 and LTE4-induced bronchoconstriction, LTD4-induced airway micro vascular leakage and LTD4-induced increase in cutaneous vascular permeability. When administered in travenously, ONO-1078 (3 30 ,u g/kg) inhibited these responses approximately 200 600 fold more potently than FPL55712. When guinea pigs were treated with indomethacin to examine the antagonism of ONO-1078 on the direct action against peptide LTs, intravenous (3 30 ,u g/kg) and oral (0.3-3 mg/kg) administration of ONO-1078 also inhibited LTC4 and LTD4-induced bronchoconstriction, and its activity was approximately 300 500 fold more potent than that of FPL55712. ONO-1078 (10 mg/kg, i.v.) had no inhibitory effect on bronchoconstrictions induced by histamine, acetylcholine, serotonin, arachidonic acid, LTB4, prostaglandin (PG) F2a , PGD2, 9a ,11,Q-PGF2, a stable thromboxane A2 mi metic agent and platelet activating factor. Furthermore, oral administration of ONO-1078 (1-10 mg/kg) inhibited slow-reacting substance of anaphylaxis mediated bronchoconstriction induced by antigen in a dose-dependent manner. These results indicate that ONO-1078 is an extremely potent, selective and orally active peptide LT antagonist and that oral administration of ONO-1078 antagonizes not only ex ogenously administered peptide LTs but also endogenous peptide LTs.

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