The cysteinyl-leukotriene receptor antagonist BAY u9773 is a competitive antagonist of leukotriene C-4 in the guinea-pig ileum

Two main classes of receptors exist for leukotrienes C-4, D-4 and E(4), collectively named cysteinyl-leukotrienes (CysLTs). The CysLT(1) receptor is blocked by currently available leukotriene antagonists, and the CysLT(2) receptor is defined by the absence of selective antagonists. The contractile response to leukotriene C-4 in guinea-pig ileum longitudinal muscle is resistant to CysLT(1) receptor antagonists. However, the leukotriene E(4) analogue BAY u9773 (6(R)-(4'-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acid) has recently been reported to inhibit CysLT(2) responses. Therefore BAY u9773 was evaluated for antagonism of the effect of leukotriene C-4 in the guinea-pig ileum longitudinal muscle. We found that BAY u9773 (0.3-10 mu M) did not contract the preparation, but produced a concentration-dependent rightward shift in the concentration-response relation for leukotriene C-4. Schild plot analysis yielded a slope which was not significantly different from unity and a pA(2) value of 6.1. The inhibition of leukotriene C-4 by BAY u9773 was not altered by antagonism of CysLT(1) receptors by ICI 198,615 {[1-[[2-methoxy-4-[[(phenylsulfonyl)amino]carbonyl]-phenyl]methyl]-1H-indazol-6-yl]carbamic acid cyclopentyl ester} (100 nM). The CysLT(1) receptor agonist, leukotriene E(4) (1 mu M), contracted the preparation but did not inhibit the contraction induced by leukotriene C-4. Taken together, the antagonism exerted by BAY u9773 appeared unrelated to actions on CysLT(1) receptors. In conclusion, BAY u9773 was a useful selective competitive antagonist of leukotriene C-4, and the findings support the classification of the receptors for leukotriene C-4 in the guinea-pig ileum as CysLT(2).