Abstract

In mammals, the endothelin (ET) family comprises three endogenous isoforms, ET-1, ET-2, and ET-3. ET-1 is the principal isoform in the human cardiovascular system and remains the most potent and long-lasting constrictor of human vessels discovered. In humans, endothelins mediate their actions via only two receptor types that have been cloned and classified as the ET_A and ET_Breceptors in the first NC-IUPHAR (International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification) report on nomenclature in 1994. This report was compiled before the discovery of the majority of endothelin receptor antagonists (particularly nonpeptides) currently used in the characterization of receptors and now updated in the present review. Endothelin receptors continue to be classified according to their rank order of potency for the three endogenous isoforms of endothelin. A selective ET_A receptor agonist has not been discovered, but highly selective antagonists include peptides (BQ123, cyclo-[d-Asp-l-Pro-d-Val-l-Leu-d-Trp-]; FR139317, N- [(hexahydro-1-azepinyl)carbonyl]l-Leu(1-Me)d-Trp-3 (2-pyridyl)-d-Ala) and the generally more potent nonpeptides, such as PD156707, SB234551, L754142, A127722, and TBC11251. Sarafotoxin S6c, BQ3020 ([Ala^11,15]Ac-ET-1_(6–21)), and IRL1620 [Suc-(Glu⁹, Ala^11,15)-ET-1_(8–21)] are widely used synthetic ET_B receptor agonists. A limited number of peptide (BQ788) and nonpeptide (A192621) ET_B antagonists have also been developed. They are generally less potent than ET_A antagonists and display lower selectivity (usually only 1 to 2 orders of magnitude) for the ET_B receptor. Radioligands highly selective for either ET_A(¹²⁵I-PD151242, ¹²⁵I-PD164333, and³H-BQ123) or ET_B receptors (¹²⁵I-BQ3020 and ¹²⁵I-IRL1620) have further consolidated classification into only these two types, with no strong molecular or pharmacological evidence to support the existence of further receptors in mammals.