In Vitro Antagonism of ONO-1078, a Newly Developed Anti-Asthma Agent, against Peptide Leukotrienes in Isolated Guinea Pig Tissues

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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_i = 0.99 and 0.63 nM, respectively) and was 2, 000- to 3, 000-fold more potent than FPL55712. Antagonism of ONO-1078 against [³H]LTC₄ binding (K_i = 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 bioconversion 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 BaCl₂-induced contractions of guinea pig trachea. Furthermore, ONO-1078 antagonized 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.