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

Abstract

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 pro®le of the cysteinyl-LT antagonists CGP 45715A (iralukast), a structural analogue of LTD 4 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 [ 3 H]-LTD 4 on human lung parenchyma membranes demonstrated that: (a) both antagonists were able to compete for the two sites labelled by [ 3 H]-LTD 4 ; (b) as in all the G-protein coupled receptors, iralukast and CGP 57698 did not discriminate between the high and the low a nity states of the CysLT receptor labelled by LTD 4 (K i1 =K i2 =16.6 nM+36% CV and K i1 = K i2 =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 LTD 4 -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 signi®cantly di erent from unity; (b) the maximal LTD 4 response in the presence of CGP 57698 was actually increased, thus clearly deviating from apparent simple competition. 5 Both antagonists signi®cantly 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 LTD 4 in human airways, with a nities 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.

Cysteinyl‐leukotriene receptor activation in brain inflammatory reactions and cerebral edema formation: a role for transcellular biosynthesis of cysteinyl leukotrienes

“…Nevertheless, the concentrations necessary for this activity appeared to be unrelated to the affinity of iralukast for bronchial cysLT1R, as we have previously reported (42).…”

CysLT1 receptor is a target for extracellular nucleotide-induced heterologous desensitization: a possible feedback mechanism in inflammation

“…Furthermore, this protein possesses the binding characteristics of a CysLT 1 receptor (Fig. 8B), with K d1 = 0.062 nM ± 24%CV and K d2 = 6.25 nM ± 27%CV, as previously reported (Capra et al, 1998a;Capra et al, 1998b;Ravasi et al, 2000) (Fig. 8D).…”

Transcellular biosynthesis of eicosanoids

“…The formation of cysteinyl leukotrienes was associated with a significant increase in wet brain weight, suggesting edema formation following neutrophil activation. As observed in the rabbit heart preparation [37], the functional effects of the alteration of vascular permeability were prevented by pretreatment of the perfused neutrophils with the inhibitor MK886 or by the dual cys-LT 1/2 receptor antagonist Bay u9773 [21], but not the selective cys-LT 1 receptor antagonist, iralukast [6]. …”