Isolated tissue and binding studies of YM-17690, a novel and non-analogous leukotriene agonist

YM-17690, 3-[4-carboxymethoxy-3-[p-(4-phenylbutoxy) benzamido]phenyl]propionic acid, produced a dose-dependent contraction of guinea-pig ileum and its EC50 value was 1.6 X 10(-8) M. The response was not affected by pretreatment with atropine, mepyramine, indomethacin, dazoxiben and AA-861 (a 5-lipoxygenase inhibitor), but was inhibited by FPL-55712 (an LTD4 and LTE4 antagonist). YM-17690 induced dose-dependent contractions of guinea-pig lung parenchyma and trachea with EC50 values of 3.9 X 10(-9) and 2.2 X 10(-8) M, respectively. Pretreatment of these tissues with FPL-55712 resulted in a parallel shift of the YM-17690 dose-response curves to the right. The pA2 values for FPL-55712 in lung parenchyma and trachea were 7.41 and 8.21, respectively, and the slopes of the regression lines of Schild plots were 1.00 and 1.02, respectively. YM-17690 produced a dose-dependent inhibition of [3H]LTD4 binding to guinea-pig lung membranes and its pKi value was 9.28. However, the compound showed only 25% inhibition of [3H]TLC4 binding to guinea-pig hippocampus membranes, even at 10(-5) M. These results suggest that YM-17690 is a selective leukotriene (LTD4 and LTE4) agonist and that it will therefore be a valuable tool in the study of actions of leukotrienes and for the characterization of their receptors.