title: Development of agonists of endothelin-1 exhibiting selectivity towards ETA 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. (4) 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 x 10(-7) vs 6.8 x 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 x 10(-6) 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).
authors.affiliation: Institut National de la Recherche Scientifique, Université du Québec, INRS-Institut Armand-Frappier, Laboratoire d'Etudes Moléculaires et Pharmacologiques des Peptides, 245 Boul. Hymus, Pointe-Claire, QC, Canada H9R 1G6.
authors.forename: Chantal
authors.initials: C
authors.lastname: Langlois
authors.forename: Myriam
authors.initials: M
authors.lastname: Létourneau
authors.forename: Philipe
authors.initials: P
authors.lastname: Lampron
authors.forename: Véronique
authors.initials: V
authors.lastname: St-Hilaire
authors.forename: Alain
authors.initials: A
authors.lastname: Fournier
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000819:agonists* / Q000031:analogs & derivatives / Q000494:pharmacology*; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects / Q000502:physiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000819:agonists* / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D019332:Endothelin-1; D044022:Receptor, Endothelin A