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Pharmacological characterization of the first potent and selective antagonist at the cysteinyl leukotriene 2 (CysLT 2 ) receptor
Author(s) -
Wunder F,
Tinel H,
Kast R,
Geerts A,
Becker EM,
Kolkhof P,
Hütter J,
Ergüden J,
Härter M
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00730.x
Subject(s) - receptor , antagonist , leukotriene d4 , chemistry , receptor antagonist , zafirlukast , pharmacology , leukotriene , cell culture , biochemistry , medicine , biology , genetics , asthma
Background and purpose: Cysteinyl leukotrienes (CysLTs) have been implicated in the pathophysiology of inflammatory and cardiovascular disorders. Their actions are mediated by CysLT 1 and CysLT 2 receptors. Here we report the discovery of 3‐({[(1S,3S)‐3‐carboxycyclohexyl]amino}carbonyl)‐4‐(3‐{4‐[4‐(cyclo‐hexyloxy)butoxy]phenyl}propoxy) benzoic acid (HAMI3379), the first potent and selective CysLT 2 receptor antagonist. Experimental approach: Pharmacological characterization of HAMI3379 was performed using stably transfected CysLT 1 and CysLT 2 receptor cell lines, and isolated, Langendorff‐perfused, guinea pig hearts. Key results: In a CysLT 2 receptor reporter cell line, HAMI3379 antagonized leukotriene D 4 ‐ (LTD 4 ‐) and leukotriene C 4 ‐ (LTC 4 ‐) induced intracellular calcium mobilization with IC 50 values of 3.8 nM and 4.4 nM respectively. In contrast, HAMI3379 exhibited very low potency on a recombinant CysLT 1 receptor cell line (IC 50 > 10 000 nM). In addition, HAMI3379 did not exhibit any agonistic activity on both CysLT receptor cell lines. In binding studies using membranes from the CysLT 2 and CysLT 1 receptor cell lines, HAMI3379 inhibited [ 3 H]‐LTD 4 binding with IC 50 values of 38 nM and >10 000 nM respectively. In isolated Langendorff‐perfused guinea pig hearts HAMI3379 concentration‐dependently inhibited and reversed the LTC 4 ‐induced perfusion pressure increase and contractility decrease. The selective CysLT 1 receptor antagonist zafirlukast was found to be inactive in this experimental setting. Conclusions and implications: HAMI3379 was identified as a potent and selective CysLT 2 receptor antagonist, which was devoid of CysLT receptor agonism. Using this compound, we showed that the cardiac effects of CysLTs are predominantly mediated by the CysLT 2 receptor.