Development of agonists of endothelin‐1 exhibiting selectivity towards ET_A receptors

Abstract

1 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. 2 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). 3 Structure -activity studies led to the identification of ET-1 fragments exhibiting an ET A selective agonistic activity. 21 ]ET-1(9 -21), showed a selective ET A activity (EC 50 : 3.0 Â 10 À6 M). None of the numerous analogues of the series exhibited substantial effects in the guinea-pig lung parenchyma bioassay. 5 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 .

The ring size of monocyclic ET‐1 controls selectivity and signaling efficiency at both endothelin receptor subtypes

“…High homology between both receptor subtypes and their ligands limits, however, the generation of selective compounds 17 . Although one ET A R‐selective agonist has been developed—[ d ‐Lys 9 ]cyclo 11–15 ET‐1(9–21)—this compound displays only weak, micromolar activity at the receptor (EC 50 : 23 μ M ) 18 . Contrary to the ET A R, several ET B R‐selective agonists have been described in literature, for example, the linear [4Ala 1,3,11,15 ]‐ET‐1, sarafotoxin 6c, IRL1620, and BQ3020 19–22 .…”

“…17 Although one ET A R-selective agonist has been developed-[D-Lys 9 ]cyclo [11][12][13][14][15] ET-1(9-21)-this compound displays only weak, micromolar activity at the receptor (EC 50 : 23 μM). 18 Contrary to the ET A R, several ET B R-selective agonists have been described in literature, for example, the linear [4Ala 1,3,11,15 ]-ET-1, sarafotoxin 6c, IRL1620, and BQ3020. [19][20][21][22] By removal of one disulfide bridge and modification of the ring size of the remaining disulfide bond, we aimed to investigate receptor selectivity and the effects on the downstream signaling profiles at both endothelin receptor subtypes.…”

Pharmacological Potential of Endothelin Receptors Agonists and Antagonists

“…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 x 10 -6 M). These peptides are the first compounds showing a significant bioactivity in an ET A pharmacological preparation while being inactive in an ET B paradigm (20).…”