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

Abstract

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 μM) 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 μM), 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.