Antagonistic action of DS-4574 against leukotrienes in guinea-pig smooth muscle.
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.
Aibara
S
S
Exploratory Research Laboratories III, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Mori
M
M
Iwamoto
T
T
Chiba
T
T
Tsukada
W
W
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D017999:Leukotriene E4; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D013189:SRS-A / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*
D000098:Acetophenones; D002867:Chromones; D011743:Pyrimidines; D013189:SRS-A; D013777:Tetrazoles; D014230:Triazoles; C076052:DS 4574; D017999:Leukotriene E4; C044660:LY 171883; C006312:FPL 55712