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

Abstract

Arachidonic acid metabolites mediate inflammatory responses at a cellular level. The affinity of the newly synthesized compound YM158, 3-[(4- tert-butylthiazol-2-yl)methoxy]-5′-[3-(4-chlorobenzenesulfonyl)propyl]-2′-(1 H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate, for leukotriene D 4 and thromboxane A 2 receptors was examined in radioligand binding assays. YM158 inhibited [ 3 H ]leukotriene D 4 and [ 3 H ]U46619 (9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F 2α) binding to guinea pig lung membrane 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 antagonism is competitive. In contrast, YM158 showed no affinity for several other receptors, including neurotransmitter-related (α 1-, α 2-, β-adrenoceptors, histamine, 5-HT, muscarinic, σ), C 5a, opioid, Ca 2+ channel, 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.