Rational Design of a Low Molecular Weight, Stable, Potent, and Long-Lasting GPR103 Aza‑β³‑pseudopeptide Agonist

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-β³-containing 26RFa_(20–26) analogues for their propensity to establish intramolecular hydrogen bonds, and we have evaluated their ability to increase [Ca²⁺]_i in GPR103-transfected cells. We have identified a compound, [Cmpi²¹,aza-β³-Hht²³]­26RFa_(21–26), which was 8-fold more potent than 26RFa_(20–26) in mobilizing [Ca²⁺]_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