Binding of YM158, a new dual antagonist for leukotriene D-4 and thromboxane A(2) receptors, to guinea pig lung membranes

Arachidonic acid metabolites mediate inflammatory responses at a cellular l evel. The affinity of the newly synthesized compound YM158, 3-[(4-terr-buty lthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenenesulfonyl)propyl]-2'-(1H-tetrazo l-5-ylmethoxy)benzanilide monosodium salt monohydrate, for leukotriene D-4 and thromboxane A(2) receptors was examined in radioligand binding assays. YM158 inhibited [H-3]leukotriene D-4 and [H-3]U46619 (9,11-dideoxy-11 alpha ,9 alpha-epoxymethanoprostaglandin F-2 alpha) binding to guinea pig lung me mbrane preparations, with K-i values of 0.64 +/- 0.06 nM for leukotriene D- 4 and 5.0 +/- 0.88 nM for thromboxane A(2) receptors. The Hill coefficients (n(H)) did not significantly differ from unity, indicating that this antag onism is competitive. In contrast, YM158 showed no affinity for several oth er receptors, including neurotransmitter-related (alpha(1)-, alpha(2)-, bet a-adrenoceptors, histamine, 5-MT, muscarinic, sigma), C-5a, opioid, Ca2+ ch annel, K+ channel, protein kinase C, bradykinin,endothelin, neurokinin and platelet activating factor receptors. These studies indicate that YM158 is a highly selective dual antagonist for leukotriene D-4 and thromboxane A(2) receptors, and this has potential clinical and research applications. (C) 1998 Elsevier Science B.V. All rights reserved.