Structure–activity relationship study on small peptidic GPR54 agonists

Metastin (kisspeptin-54) is an endogenous ligand that modulates gonadotropin-releasing hormone (GnRH) secretion through the interaction with a G protein-coupled receptor (GPCR), GPR54. The short-chain C-terminal decapeptide amide, metastin (45–54) (kisspeptin-10), exerts the identical bioactivities to metastin, such as metastasis suppression of cancer cells and inhibition of trophoblast migration and invasion. In order to understand the structural requirement for GPR54 agonistic activity, structure–activity relationship (SAR) study on pentapeptide-based C-terminal metastin analogues was carried out. As a result, H-Amb-Nal(2)-Gly-Leu-Arg-Trp-NH234 was identified as a novel GPR54 agonist that possessed the most potent GPR54 agonistic activity reported so far.

Structure–activity relationship study on GPR54 agonists was conducted based on the structures of FM052a 1 and FM053a 2. Optimization of each amino acid and the N-terminal functional group afforded a novel potent agonist 34 having a 3-(2-naphthyl)alanine.Figure optionsDownload as PowerPoint slide