Rational Design of a Low Molecular Weight, Stable, Potent, and Long-Lasting GPR103 Aza-尾3-pseudopeptide Agonist

详细信息    查看全文

• 作者：Cindy Neveu ; Benjamin Lefranc ; Olivier Tasseau ; Jean-Claude Do-Rego ; Ad猫le Bourmaud ; Philippe Chan ; Patrick Bauchat ; Olivier Le Marec ; Julien Chuquet ; Laure Guilhaudis ; Jean A. Boutin ; Isabelle S茅galas-Milazzo ; Jean Costentin ; Hubert Vaudry ; Mich猫le Baudy-Floc鈥檋 ; David Vaudry ; J茅r么me Leprince
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7516-7524
• 全文大小：387K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

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鈥?6), stimulates food intake in rodents. To develop potent, stable ligands of GPR103 with low molecular weight, we have designed a series of aza-尾³-containing 26RFa_(20鈥?6) 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-尾³-Hht²³]26RFa_(21鈥?6), which was 8-fold more potent than 26RFa_(20鈥?6) in mobilizing [Ca²⁺]_i. This pseudopeptide was more stable in serum than 26RFa_(20鈥?6) 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.