Structure-activity relationship study and NMR analysis of fluorobenzoyl pentapeptide GPR54 agonists

Biopolymers. 2008;90(4):503-11. doi: 10.1002/bip.20968.


GPR54 is a Gq-protein coupled receptor involved in cancer metastasis and regulation of the endocrine system. GPR54 activation by endogenous ligands attenuates the mobility of carcinomas and stimulates the secretion of gonadotropin-releasing hormone. GPR54 agonists are, therefore, potential therapeutic candidates for cancer metastasis and hormonal diseases. Pentapeptide derivatives of kisspeptin C-terminus were identified as potent GPR54 agonists in our previous studies. In the present study, we investigated the structure-activity relationship of a variety of pentapeptides having various fluorine-substituted benzoyl groups at the N-terminus. Among these, a 4-fluorobenzoyl derivative was the most potent agonist. On the other hand, the derivatives having multiple fluoro-substituting groups showed less binding affinity. NMR analysis of these peptides and their N-terminal partial structures suggested that fluorine substituents affect the benzoyl conformation. o-Monofluorobenzoyl is likely to be in a coplanar conformation due to the intramolecular CF--HN hydrogen bonding between o-fluorine and amide hydrogen; the o,o-difluorobenzoyl moiety exists in a distorted conformation probably due to the steric hindrance and/or electrostatic repulsion between two o-fluorine atoms and carbonyl oxygen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Fluorobenzenes / chemistry*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Molecular Conformation
  • Molecular Sequence Data
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacology*
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, Kisspeptin-1
  • Structure-Activity Relationship


  • Fluorobenzenes
  • KISS1R protein, human
  • Oligopeptides
  • Receptors, G-Protein-Coupled
  • Receptors, Kisspeptin-1