Pharmacological differences among CysLT1 receptor antagonists with respect to LTC4 and LTD4 in human lung parenchyma

We have previously reported, by means of equilibrium binding studies, the existence of two distinct binding sites with receptor characteristics for LTC4 and LTD4 in human lung parenchyma (HLP) membranes using S-decyl-glutathione (S-decyl-GSH) to inhibit LTC4 binding to a number of non-receptor sites. Recently, we have been able to avoid the use of S-decyl-GSH in kinetic experiments and to characterize a distinctive pharmacological profile for the LTC4 high affinity binding sites which do not correlates with the ability of both LTD4 and LTC4 to contract isolated HLP strips through the CysLT(1) receptor. Here, we report that the most advanced CysLT(1) receptor antagonists, some of which are already in clinical use, displayed a different behavior toward LTC4 and LTD4 in HLP. Equilibrium and kinetic binding studies demonstrated the following rank order of potency for H-3-LTD4 receptor (CysLT(1)): zafirlukast = montelukast > LM-1507 = LM-1484 = pranlukast. In addition, LM-1507, LM-1484, pranlukast and montelukast but not zafirlukast are able to interact also with the high affinity site for H-3-LTC4, (LM-1507 = LM-1484 > pranlukast; montelukast not detectable in the presence of S-decyl-GSH). In this respect, the behavior of the LM antagonists closely resembles that of pranlukast although LM-1507 and LM-1484 display a higher affinity for H-3-LTC4 Sites, Montelukast has an intermediate behavior, inasmuch as its interaction with H-3-LTC4 sites can be revealed only in kinetic studies, while zafirlukast is totally unable to inhibit 3 H-3-LTC4 binding. It might be, therefore, most relevant for a complete understanding of the clinical efficacy, besides their nominal potency, of the most advanced CysLT, receptor antagonists to consider their pharmacological differences with respect not only to LTD4/LTE4, but also to LTC4. (C) 2002 Elsevier Science Inc. All rights reserved.