Antagonistic action of DS-4574 against leukotrienes in guinea-pig smooth muscle

Abstract

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.