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

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. © 2008 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 503–511, 2008.