Structure-activity relationships of a novel series of urotensin II analogues: identification of a urotensin II antagonist

David Chatenet, Christophe Dubessy, Cédric Boularan, Elizabeth Scalbert, Bruno Pfeiffer, Pierre Renard, Isabelle Lihrmann, Pierre Pacaud, Marie-Christine Tonon, Hubert Vaudry, Jérôme Leprince
Journal of Medicinal Chemistry 2006 November 30, 49 (24): 7234-8
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.


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