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

J Med Chem. 2006 Nov 30;49(24):7234-8. doi: 10.1021/jm0602110.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Humans
  • In Vitro Techniques
  • Peptide Fragments / chemical synthesis*
  • Peptide Fragments / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / genetics
  • Structure-Activity Relationship
  • Urotensins / antagonists & inhibitors*
  • Urotensins / chemical synthesis*
  • Urotensins / pharmacology
  • Vasodilator Agents / chemical synthesis*
  • Vasodilator Agents / pharmacology


  • Peptide Fragments
  • Receptors, G-Protein-Coupled
  • UTS2R protein, human
  • Urotensins
  • Vasodilator Agents
  • urotensin II(4-11), Cha(6)-
  • urotensin II