Development of agonists of endothelin‐1 exhibiting selectivity towards ET A receptors

Endothelin‐1 (ET‐1) is a bicyclic 21‐amino‐acid peptide causing a potent and sustained vasoconstriction, mainly through the ET A receptor subtype. So far, no selective ET A agonists are described in the literature. A series of truncated and chemically modified ET‐1 analogues were obtained through solid‐phase peptide synthesis and their biological activity was assessed on rat thoracic aorta rings (ET A receptors) and guinea‐pig lung parenchyma strips (ET B receptors). Structure–activity studies led to the identification of ET‐1 fragments exhibiting an ET A selective agonistic activity. In particular, [ D ‐Lys 9 ]cyclo 11–15 ET‐1(9–21) was the most potent peptide. It appeared as a full agonist of ET A receptors, being under two orders of magnitude less potent than ET‐1 (EC 50 : 2.3 × 10 −7 vs 6.8 × 10 −9 M ). Interestingly, even a linear formylated analogue, [Ala 11,15 , Trp(For) 21 ]ET‐1(9–21), showed a selective ET A activity (EC 50 : 3.0 × 10 −6 M ). None of the numerous analogues of the series exhibited substantial effects in the guinea‐pig lung parenchyma bioassay. Thus, this study describes the first compounds showing a significant bioactivity in an ET A pharmacological preparation while being inactive in an ET B paradigm. They show that the ET‐1 pharmacophores, responsible for the ET A ‐mediated actions, are located within the 9–21 segment of the molecule. Moreover, the bicyclic structure of ET‐1 does not appear as essential for the ET A ‐related vasoconstriction. Results also suggest that the positive charge of the Lys 9 side chain participates in an intramolecular ionic bond with the carboxylate function of Asp 18 .British Journal of Pharmacology (2003) 139 , 616–622. doi: 10.1038/sj.bjp.0705252