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

Abstract

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.

Cysteinyl Leukotrienes Induce Nasal Symptoms of Allergic Rhinitis via a Receptor-Mediated Mechanism in Guinea Pigs

“…This is the first demonstration of the existence of cysLTs receptor in the nasal mucosa. It should be noted that Kd and Bmax values for [3H]LTC4i [3H]LTD4 and [3H]LTE4 in this study are similar to those previously reported with membrane fractions of guinea pig lung (6). Therefore, it appears that the affinity and distribution of receptors for cysLTs is similar between upper and lower airways.…”

Do Mucosal Mast Cells Contribute to the Immediate Asthma Response?

“…Since rat trachea was found to be insensitive to histamine (5), due to the lack of H1 receptors in rat trachea, the possible anti-histamine action of ketanserin might be excluded. ONO-1078 at the same concentration was reported to inhibit contraction of guinea pig trachea and lung parenchymal strips induced by LTC4 and LTD4 (29). It is interesting to note that LTD4 had no significant effect, since both types of mast cells could be stimulated by immunologic stimuli, and MMCs are capable of releasing leukotriene (6).…”

Characterization of Mouse Cysteinyl Leukotriene Receptors mCysLT1 and mCysLT2

“…Most of the biological reactions of cysteinyl LTs including bronchospasm, plasma exudation, vasoconstriction, mucus secretion, and eosinophil recruitment are mediated through interaction with CysLT 1 (11). CysLT 1 antagonists, montelukast (Singulair TM ) (12,13), zafirlukast (Accolate TM ) (14), and pranlukast (Onon TM ) (15) are currently used clinically for the treatment of bronchial asthma and allergic rhinitis. Human CysLT 1 , human CysLT 2 , and mouse CysLT 1 were recently cloned and characterized (16 -21).…”