Identification of nonpeptidic urotensin II receptor antagonists by virtual screening based on a pharmacophore model derived from structure-activity relationships and nuclear magnetic resonance studies on urotensin II

J Med Chem. 2002 Apr 25;45(9):1799-805. doi: 10.1021/jm0111043.


The vasoactive cyclic 11-amino acid peptide urotensin II (U-II) has recently been discovered as the endogenous ligand of the orphan G-protein-coupled receptor GPR14. As U-II might be involved in the regulation of cardiovascular homeostasis and pathology, a nonpeptidic GPR14/U-II antagonist is of considerable basic and therapeutic interest. We have performed structure-activity relationship studies on U-II by investigating 25 peptide analogues to mobilize intracellular calcium in GPR14-transfected CHO cells, demonstrating that only the side chains of the residues Trp-7, Lys-8, and Tyr-9 are required for receptor recognition and activation. The solution structure of U-II derived by nuclear magnetic resonance has served as a structural template for a three-dimensional three point pharmacophore query for the virtual screening of the Aventis compound repository for nonpeptidic U-II receptor antagonists. Highly active lead compounds of six different scaffold classes could be identified, antagonizing the biological activity of U-II in vitro. The most potent compound identified by the virtual screening approach, 1-(3-carbamimidoyl-benzyl)-4-methyl-1H-indole-2-carboxylic acid (naphthalen-1-ylmethyl)amide, reveals an IC(50) of 400 nM in a functional fluorometric imaging plate reader assay and constitutes a promising lead.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • CHO Cells
  • Calcium / metabolism
  • Combinatorial Chemistry Techniques
  • Cricetinae
  • Databases, Factual
  • Fluorometry
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology
  • Peptide Fragments / chemical synthesis*
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / metabolism
  • Receptors, G-Protein-Coupled*
  • Structure-Activity Relationship
  • Transfection
  • Urotensins / chemistry*


  • 1-(3-carbamimidoyl-benzyl)-4-methyl-1H-indole-2-carboxylic acid(naphthalen-1-ylmethyl)amide
  • Indoles
  • Ligands
  • Naphthalenes
  • Peptide Fragments
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • UTS2R protein, human
  • Urotensins
  • urotensin II
  • Calcium