Structure-activity relationships of a series of analogues of the RFamide-related peptide 26RFa

摘要

26RFa is a new member of the RFamide peptide family that has been identified as the endogenous ligand of the orphan GPCR GPR103. As the C-terminal heptapeptide (26RFa_((20-26))) mimics the action of the native peptide on food intake and gonadotropin secretion in rodents, we have synthesized a series of analogues of 26RFa_((20-26)) and measured their potency to induce [Ca~(2+)]_i mobilization in Gα_(16)- hGPR103-transfected CHO cells. Systematic replacement of each residue by an alanine (Ala scan) and its d-enantiomer (d scan) showed that the last three C-terminal residues were very sensitive to the substitutions while position 23 tolerated rather well both modifications. Most importantly, replacement of Ser~(23) by a norvaline led to an analogue, [Nva~(23)]26RFa _((20-26)), that was 3-fold more potent than the native heptapeptide. These new pharmacological data, by providing the first information regarding the structure-activity relationships of 26RFa analogues, should prove useful for the rational design of potent GPR103 receptor ligands with potential therapeutic application.