Pharmacological differences among CysLT 1 receptor antagonists with respect to LTC 4 and LTD 4 in human lung parenchyma

Abstract

We have previously reported, by means of equilibrium binding studies, the existence of two distinct binding sites with receptor characteristics for LTC 4 and LTD 4 in human lung parenchyma (HLP) membranes using S-decyl-glutathione ( S-decyl-GSH) to inhibit LTC 4 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 LTC 4 high affinity binding sites which do not correlates with the ability of both LTD 4 and LTC 4 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 LTC 4 and LTD 4 in HLP. Equilibrium and kinetic binding studies demonstrated the following rank order of potency for 3 H -LTD 4 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 3 H -LTC 4 (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 3 H -LTC 4 sites. Montelukast has an intermediate behavior, inasmuch as its interaction with 3 H -LTC 4 sites can be revealed only in kinetic studies, while zafirlukast is totally unable to inhibit 3 H -LTC 4 binding. It might be, therefore, most relevant for a complete understanding of the clinical efficacy, besides their nominal potency, of the most advanced CysLT 1 receptor antagonists to consider their pharmacological differences with respect not only to LTD 4/LTE 4, but also to LTC 4.