Defining the affinity and receptor sub-type selectivity of four classes of endothelin antagonists in clinically relevant human cardiovascular tissues

[摘要] Aims: We have compared the endothelin receptor subtype affinity (K-D) and selectivity of four structural classes of antagonists (peptide, sulphonamide-based, carboxylic acid-based, myceric acid-based) in human cardiovascular tissues to determine whether these are predicted by values reported for human cloned receptors. Additionally, affinities (K-B) for these antagonists, determined in ET-1-mediated vasoconstriction assays in human blood vessels, were used to identify discrepancies between K-B and K-D determined in the same tissues. Main methods: Competition binding experiments were carried out in sections of human left ventricle, coronary artery and homogenates of saphenous vein to determine K-D values for structurally different ETA-selective (FR139317, BMS 182874, S97-139, sitaxentan, ambrisentan) and mixed (PD142893, Ro462005, bosentan, L-749329, SB209670) antagonists. Schild-derived values of antagonist affinity were obtained in vascular functional studies. Key findings: When compared with previously reported data in human cloned endothelin receptors, those antagonists reported to be ETA-selective exhibited even greater ETA selectivity in human ventricle (BMS 182874, sitaxentan, ambrisentan) that expressed both receptor subtypes. Those antagonists reported to have <100 fold selectivity in cloned receptors (PD142893, Ro-462005, bosentan, SB209670, L-749329) did not distinguish between receptor subtypes in human left ventricle. For antagonists where we determined affinity in vascular functional and binding assays (Ro462005, bosentan, BMS 182874, L-749329. SB209670) there was no correlation between the degree of discrepancy in K-B and K-D and structural class. Significance: For an antagonist to retain ETA-selectivity in vivo it may be necessary to identify those compounds that have at least 1000 fold ETA:ETB selectivity in in vitro assays. (c) 2012 Elsevier Inc. All rights reserved.

[发布日期] 2012-10-15

[效力级别]  Proceedings Paper

[关键词] ET-1;ETA;ETB;Human cardiovascular;Pharmacology;Affinity;Endothelin receptor selectivity;Vasoconstriction;Human coronary artery;Human left ventricle;Human saphenous vein