Aibara S, Mori M, Iwamoto T, Chiba T, Tsukada W
Exploratory Research Laboratories III, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Arch Int Pharmacodyn Ther. 1991 Nov-Dec;314:147-59.
We investigated the effect of a new antiallergic agent, DS-4574, on the guinea-pig smooth muscle contractions induced by leukotriene C4, D4 and E4 (LTC4, D4 and E4) in vitro. In isolated guinea-pig ileum, DS-4574 antagonized the contraction induced by LTC4, LTD4 and LTE4 with IC50 values of 3.5 x 10(-7), 2.0 x 10(-7) and 2.6 x 10(-7) M, respectively. In contrast, at 10(-4) M this compound inhibited the contractions induced by histamine, acetylcholine, 5-hydroxytryptamine, bradykinin and prostaglandin F2 alpha by less than 50%. In isolated tracheal strip preparations of guinea-pigs, DS-4574 produced a parallel concentration-dependent rightward shift of the leukotriene concentration-response curves without affecting the maximal response. The dissociation constant of DS-4574, obtained against LTC4, LTD4 and LTE4, was 3.07 +/- 0.47 x 10(-8), 1.81 +/- 0.36 x 10(-8) and 7.30 +/- 3.40 x 10(-8) M, respectively. The slopes of Schild plots for DS-4574 against leukotrienes did not differ significantly from unity. In the presence of an inhibitor of the metabolism of LTC4 to LTD4, about 100 times higher concentrations of DS-4574 were required to antagonize LTC4-induced contractions. Moreover, DS-4574 competed with the [3H]LTD4-, [3H]LTE4- and [3H]LTC4-specific binding to the receptor in guinea-pig lung membranes with Ki values of 7.2 x 10(-7), 4.5 x 10(-7) and 3.9 x 10(-5) M, respectively. The present data suggest that DS-4574 is a selective and competitive leukotriene antagonist. When the leukotriene antagonism by DS-4574 is confirmed in other species, it might be useful in a variety of diseases associated with excessive production of leukotrienes.
我们研究了一种新型抗过敏药物DS - 4574对体外白三烯C4、D4和E4（LTC4、D4和E4）诱导的豚鼠平滑肌收缩的影响。在离体豚鼠回肠中，DS - 4574拮抗LTC4、LTD4和LTE4诱导的收缩，IC50值分别为3.5×10⁻⁷、2.0×10⁻⁷和2.6×10⁻⁷M。相比之下，在10⁻⁴M时，该化合物对组胺、乙酰胆碱、5 - 羟色胺、缓激肽和前列腺素F2α诱导的收缩的抑制作用小于50%。在豚鼠离体气管条制备物中，DS - 4574使白三烯浓度 - 反应曲线产生平行的浓度依赖性右移，而不影响最大反应。针对LTC4、LTD4和LTE4获得的DS - 4574的解离常数分别为3.07±0.47×10⁻⁸、1.81±0.36×10⁻⁸和7.30±3.40×10⁻⁸M。DS - 4574对白三烯的Schild图斜率与1无显著差异。在存在将LTC4代谢为LTD4的抑制剂的情况下，拮抗LTC4诱导的收缩需要约100倍更高浓度的DS - 4574。此外，DS - 4574与豚鼠肺膜中[³H]LTD4 -、[³H]LTE4 - 和[³H]LTC4与受体的特异性结合竞争，Ki值分别为7.2×10⁻⁷、4.5×10⁻⁷和3.9×10⁻⁵M。目前的数据表明DS - 4574是一种选择性和竞争性白三烯拮抗剂。当DS - 4574对白三烯的拮抗作用在其他物种中得到证实时，它可能对多种与白三烯过度产生相关的疾病有用。
