title: Development and pharmacological characterization of conformationally constrained urotensin II-related peptide agonists.
abstract: Urotensin II (UII) and its paralog peptide, urotensin II-related peptide (URP), exert not only common but also divergent actions through the activation of UT, a specific membrane-bound receptor that belongs to the 1A G protein-coupled receptor subclass. In this study, we have designed and synthesized new URP analogues in which the intracyclic Trp residue was replaced with natural, unnatural, and constrained amino acids to determine important physicochemical features for receptor binding and activation. The biological data, highlighting the potent agonistic behavior of [Tiq(4)]URP and [Tpi(4)]URP, also suggest that the Trp residue, and more specifically the indole ring, is not critical for receptor interaction and could in fact be involved in the intramolecular stabilization of the bioactive conformation of URP. Finally, these analogues, which are intracyclic constrained URP-based agonists, could represent useful pharmacological tools for the study of the urotensinergic system.
authors.affiliation: INRS-Institut Armand-Frappier, Institut national de la recherche scientifique, Université du Québec , Ville de Laval, Québec, QC H7V 1B7, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Chatenet
authors.forename: Benjamin
authors.initials: B
authors.lastname: Folch
authors.forename: Debby
authors.initials: D
authors.lastname: Feytens
authors.forename: Myriam
authors.initials: M
authors.lastname: Létourneau
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwé
authors.forename: Nicolas
authors.initials: N
authors.lastname: Doucet
authors.forename: Alain
authors.initials: A
authors.lastname: Fournier
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D056004:Molecular Dynamics Simulation; D036361:Peptide Hormones / Q000819:agonists* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D014579:Urotensins / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D036361:Peptide Hormones; C479080:UTS2B protein, human; D014579:Urotensins; C029677:urotensin II