| Abstract
| - 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.
|
