Rational design of a low molecular weight, stable, potent, and long-lasting GPR103 Aza-β ~3-pseudopeptide agonist

摘要

26RFa, a novel RFamide neuropeptide, is the endogenous ligand of the former orphan receptor GPR103. Intracerebroventricular injection of 26RFa and its C-terminal heptapeptide, 26RFa _(20-26), stimulates food intake in rodents. To develop potent, stable ligands of GPR103 with low molecular weight, we have designed a series of aza-β ~3-containing 26RFa _((20-26)) analogues for their propensity to establish intramolecular hydrogen bonds, and we have evaluated their ability to increase [Ca ~(2+)] _i in GPR103-transfected cells. We have identified a compound, [Cmpi ~(21),aza-β ~3-Hht _(23)]26RFa _((21-26)), which was 8-fold more potent than 26RFa _((20-26)) in mobilizing [Ca ~(2+)] _i. This pseudopeptide was more stable in serum than 26RFa _((20-26)) and exerted a longer lasting orexigenic effect in mice. This study constitutes an important step toward the development of 26RFa analogues that could prove useful for the treatment of feeding disorders.