title: Structure-activity relationships of a novel series of urotensin II analogues: identification of a urotensin II antagonist.
abstract: Urotensin II (U-II) is a potent vasoconstrictor peptide which has been identified as the endogenous ligand for the orphan G protein-coupled receptor GPR14 now renamed UT receptor. As the C-terminal cyclic hexapeptide of U-II (U-II(4-11), H-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH) possesses full biological activity, we have synthesized a series of U-II(4-11) analogues and measured their binding affinity on hGPR14-transfected CHO cells and their contractile activity on de-endothelialized rat aortic rings. The data indicate that a free amino group and a functionalized side-chain at the N-terminal extremity of the peptide are not required for biological activity. In addition, the minimal chemical requirement at position 9 of U-II(4-11) is the presence of an aromatic moiety. Most importantly, replacement of the Phe6 residue by cyclohexyl-Ala (Cha) led to an analogue, [Cha6]U-II(4-11), that was devoid of agonistic activity but was able to dose-dependently suppress the vasoconstrictor effect of U-II on rat aortic rings. These new pharmacological data, by providing further information regarding the structure-activity relationships of U-II analogues, should prove useful for the rational design of potent and nonpeptidic UT receptor agonists and antagonists.
authors.affiliation: INSERM U413, Laboratory of Cellular & Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), University of Rouen, 76821 Mont-Saint-Aignan, France.
authors.forename: David
authors.initials: D
authors.lastname: Chatenet
authors.forename: Christophe
authors.initials: C
authors.lastname: Dubessy
authors.forename: Cédric
authors.initials: C
authors.lastname: Boularan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Scalbert
authors.forename: Bruno
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lihrmann
authors.forename: Pierre
authors.initials: P
authors.lastname: Pacaud
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Tonon
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
authors.forename: Jérôme
authors.initials: J
authors.lastname: Leprince
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D066298:In Vitro Techniques; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics; D013329:Structure-Activity Relationship; D014579:Urotensins / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis* / Q000494:pharmacology; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; D014579:Urotensins; D014665:Vasodilator Agents; C517065:urotensin II(4-11), Cha(6)-; C029677:urotensin II