Pharmacological characterization of the cysteinyl-leukotriene antagonists CGP 45715A (iralukast) and CGP 57698 in human airways in vitro

Br J Pharmacol. 1998 Feb;123(3):590-8. doi: 10.1038/sj.bjp.0701636.


1. Cysteinyl-leukotrienes (cysteinyl-LTs) are important mediators in the pathogenesis of asthma. They cause bronchoconstriction, mucus hypersecretion, increase in microvascular permeability, plasma extravasation and eosinophil recruitment. 2. We investigated the pharmacological profile of the cysteinyl-LT antagonists CGP 45715A (iralukast), a structural analogue of LTD4 and CGP 57698, a quinoline type antagonist, in human airways in vitro, by performing binding studies on human lung parenchyma membranes and functional studies on human isolated bronchial strips. 3. Competition curves vs [3H]-LTD4 on human lung parenchyma membranes demonstrated that: (a) both antagonists were able to compete for the two sites labelled by [3H]-LTD4; (b) as in all the G-protein coupled receptors, iralukast and CGP 57698 did not discriminate between the high and the low affinity states of the CysLT receptor labelled by LTD4 (Ki1=Ki2= 16.6 nM+/-36% CV and Ki1= Ki2 = 5.7 nM+/-19% CV, respectively); (c) iralukast, but not CGP 57698, displayed a slow binding kinetic, because preincubation (15 min) increased its antagonist potency. 4. In functional studies: (a) iralukast and CGP 57698 antagonized LTD4-induced contraction of human bronchi, with pA2 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 of CGP 57698 was actually increased, thus clearly deviating from apparent simple competition. 5. Both antagonists significantly inhibited antigen-induced contraction of human isolated bronchial strips in a concentration-dependent manner, lowering the upper plateau of the anti-IgE curves. 6. In conclusion, the results of the present in vitro investigation indicate that iralukast and CGP 57698 are potent antagonists of LTD4 in human airways, with affinities in the nanomolar range, similar to those obtained for ICI 204,219 and ONO 1078, two of the most clinically advanced CysLT receptor antagonists. Thus, these compounds might be useful drugs for the therapy of asthma and other allergic diseases.

MeSH terms

  • Antigens / immunology
  • Benzopyrans / metabolism
  • Benzopyrans / pharmacology*
  • Binding, Competitive
  • Bronchi / drug effects*
  • Bronchi / metabolism
  • Bronchi / physiology
  • Humans
  • In Vitro Techniques
  • Leukotriene D4 / antagonists & inhibitors*
  • Leukotriene D4 / metabolism
  • Lung / drug effects*
  • Lung / metabolism
  • Muscle Contraction / drug effects
  • Muscle Contraction / immunology


  • Antigens
  • Benzopyrans
  • Leukotriene D4
  • iralukast