Structure-Activity Relationships of a Novel Series of Urotensin II Analogues: Identification of a Urotensin II Antagonist

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• 作者：David Chatenet ; Christophe Dubessy ; Cé ; dric Boularan ; Elizabeth Scalbert ; Bruno Pfeiffer ; Pierre Renard ; Isabelle Lihrmann ; Pierre Pacaud ; Marie-Christine Tonon ; Hubert Vaudry ; Jé ; rô ; m
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：November 30, 2006
• 年：2006
• 卷：49
• 期：24
• 页码：7234 - 7238
• 全文大小：60K
• 年卷期：v.49,no.24(November 30, 2006)
• ISSN：1520-4804

文摘

Urotensin II (U-II) is a potent vasoconstrictor peptide which has been identified as the endogenous ligandfor the orphan G protein-coupled receptor GPR14 now renamed UT receptor. As the C-terminal cyclichexapeptide 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-transfectedCHO cells and their contractile activity on de-endothelialized rat aortic rings. The data indicate that a freeamino group and a functionalized side-chain at the N-terminal extremity of the peptide are not required forbiological activity. In addition, the minimal chemical requirement at position 9 of U-II_(4-11) is the presenceof an aromatic moiety. Most importantly, replacement of the Phe⁶ residue by cyclohexyl-Ala (Cha) led toan analogue, [Cha⁶]U-II_(4-11), that was devoid of agonistic activity but was able to dose-dependently suppressthe vasoconstrictor effect of U-II on rat aortic rings. These new pharmacological data, by providing furtherinformation regarding the structure-activity relationships of U-II analogues, should prove useful for therational design of potent and nonpeptidic UT receptor agonists and antagonists.