PHARMACOLOGICAL CHARACTERIZATION OF THE CYSTEINYL-LEUKOTRIENE ANTAGONISTS CGP-45715A (IRALUKAST) AND CGP-57698 IN HUMAN AIRWAYS IN-VITRO

1 Cysteinyl-leukotrienes (cysteinyl-LTs) are important mediators in th e pathogenesis of asthma. They cause bronchoconstriction, mucus hypers ecretion. increase in microvascular permeability, plasma extravasation and eosinophil recruitment. 2 We investigated the pharmacological pro file of the cysteinyl-LT antagonists CGP 45715A (iralukast), a structu ral analogue of LTD, and CGP 57698, a quinoline type antagonist, in hu man airways in vitro, by performing binding studies on human lung pare nchyma membranes and functional studies on human isolated bronchial st rips. 3 Competition curves vs [H-3]-LTD4 on human lung parenchyma memb ranes demonstrated that: (a) both antagonists were able to compete for the two sites labelled by [H-3]-LTD4 (b) as in all the G-protein coup led receptors, iralukast and CGP 57698 did not discriminate between th e high and the low affinity states of the CysLT receptor labelled by L TD4 (K-11=k(12)=16.6nM+/-36% CV and K-11 = k(12)=5.7 nM+/-19% CV, resp ectively); (c) iralukast, but not CGP 57698, displayed a slow binding kinetic, because preincubation (15 min) increased its antagonist poten cy. 4 In functional studies: (a) iralukast and CGP 57698 antagonized L TD4-induced contraction of human bronchi, with pA(2) values of 7.77+/- 4.3% CV and 8.51+/-1.6% CV, respectively, and slopes not significantly different from unity; (b) the maximal LTD4 response in the presence o f CGP 57698 was actually increased, thus clearly deviating from appare nt simple competition. 5 Both antagonists significantly inhibited anti gen-induced contraction of human isolated bronchial strips in a concen tration-dependent manner, lowering the upper plateau of the anti-IgE c urves. 6 In conclusion. the results of the present in vitro investigat ion indicate that iralukast and CGP 57698 are potent antagonists of LT D, in human airways, with affinities in the nanomolar range, similar t o those obtained for ICI 204.219 and ONO 1078, two of the most clinica lly advanced CysLT receptor antagonists. Thus, these compounds might b e useful drugs for the therapy of asthma and other allergic diseases.