The cysteinyl-leukotriene receptor antagonist BAY u9773 is a competitive antagonist of leukotriene C4 in the guinea-pig ileum.

Two main classes of receptors exist for leukotrienes C4, D4 and E4, collectively named cysteinyl-leukotrienes (CysLTs). The CysLT1 receptor is blocked by currently available leukotriene antagonists, and the CysLT2 receptor is defined by the absence of selective antagonists. The contractile response to leukotriene C4 in guinea-pig ileum longitudinal muscle is resistant to CysLT1 receptor antagonists. However, the leukotriene E4 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 CysLT2 responses. Therefore BAY u9773 was evaluated for antagonism of the effect of leukotriene C4 in the guinea-pig ileum longitudinal muscle. We found that BAY u9773 (0.3-10 microM) did not contract the preparation, but produced a concentration-dependent rightward shift in the concentration-response relation for leukotriene C4. Schild plot analysis yielded a slope which was not significantly different from unity and a pA2 value of 6.1. The inhibition of leukotriene C4 by BAY u9773 was not altered by antagonism of CysLT1 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 CysLT1 receptor agonist, leukotriene E4 (1 microM), contracted the preparation but did not inhibit the contraction induced by leukotriene C4. Taken together, the antagonism exerted by BAY u9773 appeared unrelated to actions on CysLT1 receptors. In conclusion, BAY u9773 was a useful selective competitive antagonist of leukotriene C4, and the findings support the classification of the receptors for leukotriene C4 in the guinea-pig ileum as CysLT2.