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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.
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https://hal-normandie-univ.archives-ouvertes.fr/hal-01960843
Contributor : Jérôme Leprince <>
Submitted on : Wednesday, December 19, 2018 - 3:48:29 PM
Last modification on : Wednesday, May 6, 2020 - 1:30:29 AM

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David Chatenet, Christophe Dubessy, Cédric Boularan, Elizabeth Scalbert, Bruno Pfeiffer, et al.. Structure−Activity Relationships of a Novel Series of Urotensin II Analogues: Identification of a Urotensin II Antagonist. Journal of Medicinal Chemistry, American Chemical Society, 2006, 49 (24), pp.7234-7238. ⟨10.1021/jm0602110⟩. ⟨hal-01960843⟩

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