Design, synthesis, conformational analysis, and biological studies of urotensin-II lactam analogues

Bioorg Med Chem. 2002 Dec;10(12):3731-9. doi: 10.1016/s0968-0896(02)00372-3.

Abstract

Human urotensin II (hU-II; H-Glu-Thr-Pro-Asp-cyclo[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) is a disulfide bridged undecapeptide recently identified as the ligand of an orphan G protein-coupled receptor. hU-II has been described as the most potent vasoconstrictor compound identified to date. With the aim of replacing the disulfide bridge by a chemically more stable moiety, we have synthesized and tested a series of lactam analogues of hU-II minimum active fragment, that is hU-II(4-11). The contractile activity of the synthetic analogues on the rat isolated thoracic aorta was found to be dependent upon the dimension of the lactam bridge. The most active peptide, H-Asp-cyclo[Orn-Phe-Trp-Lys-Tyr-Asp]-Val-OH (3), is approximately 2 logs less potent than hU-II (pD(2)=6.3 vs 8.4). A conformational analysis in solution of the active peptide 3, one of the inactive analogues, and hU-II was performed, using NMR and molecular modelling techniques. A superposition of the calculated structures of hU-II and 3 clearly shows that three out of four key residues (i.e., Phe(6), Lys(8) and Tyr(9)) maintain the same side- chain orientation, while the fourth one, Trp(7), cannot be superimposed. This observation could explain the reduced biological activity of the synthetic analogue.

MeSH terms

  • Animals
  • Aorta / drug effects
  • Drug Design
  • Drug Stability
  • Humans
  • Lactams / chemical synthesis
  • Lactams / chemistry
  • Lactams / pharmacology*
  • Male
  • Models, Molecular
  • Molecular Conformation
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • Urotensins / chemistry*
  • Urotensins / pharmacology
  • Vasoconstrictor Agents / chemical synthesis*
  • Vasoconstrictor Agents / chemistry
  • Vasoconstrictor Agents / pharmacology

Substances

  • Lactams
  • Peptides, Cyclic
  • Urotensins
  • Vasoconstrictor Agents
  • urotensin II