In Vitro Antagonism of ONO-1078, a Newly Developed Anti-Asthma Agent, against Peptide Leukotrienes in Isolated Guinea Pig Tissues.
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概要
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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 [<SUP>3</SUP>H]LTD<SUB>4</SUB> and [<SUP>3</SUP>H]LTE<SUB>4</SUB> bindings to lung membranes (K<SUB>i</SUB> = 0.99 and 0.63 nM, respectively) and was 2, 000- to 3, 000-fold more potent than FPL55712. Antagonism of ONO-1078 against [<SUP>3</SUP>H]LTC<SUB>4</SUB> binding (K<SUB>i</SUB> = 5640 nM) was approximately twofold more potent than that of FPL55712. The antagonism of ONO-1078 against [<SUP>3</SUP>H]LTD<SUB>4</SUB> binding was competitive. In functional experiments, ONO-1078 showed competitive antagonism against the LTC<SUB>4</SUB>- and LTD<SUB>4</SUB>-induced contractions of guinea pig trachea and lung parenchymal strips with a pA<SUB>2</SUB> 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 LTC<SUB>4</SUB> to LTD<SUB>4</SUB>, ONO-1078 also antagonized the LTC<SUB>4</SUB>-induced contraction of guinea pig trachea (pA<SUB>2</SUB> = 7.78). ONO-1078 significantly reversed the LTD<SUB>4</SUB>-induced prolonged contraction without effect on the KCl- and BaCl<SUB>2</SUB>-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 D<SUB>2</SUB> 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 LTD<SUB>4</SUB> and LTE<SUB>4</SUB> receptors than LTC<SUB>4</SUB> receptors.
- 公益社団法人 日本薬理学会の論文
著者
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Nakagawa Naoki
Minase Research Institute Ono Pharmaceutical Co. Ltd.
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OBATA Takaaki
Minase Research Institute, Ono Pharmaceutical Co., Ltd.
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Aishita Hideki
Minase Research Institute, Ono Pharmaceutical Co., Ltd.
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Okada Yutaka
Minase Research Institute, Ono Pharmaceutical Co., Ltd.
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Terawaki Tamiya
Minase Research Institute, Ono Pharmaceutical Co., Ltd.
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Motoishi Mariko
Minase Research Institute, Ono Pharmaceutical Co., Ltd.
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- In Vivo Pharmacologic Profile of ONO-1078: A Potent, Selective and Orally Active Peptide Leukotriene (LT) Antagonist.
- In Vitro Antagonism of ONO-1078, a Newly Developed Anti-Asthma Agent, against Peptide Leukotrienes in Isolated Guinea Pig Tissues.
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