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-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.
Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), INSERM U982, 76821 Mont-Saint-Aignan, France.
Cindy
C
Neveu
Benjamin
B
Lefranc
Olivier
O
Tasseau
Jean-Claude
JC
Do-Rego
Adèle
A
Bourmaud
Philippe
P
Chan
Patrick
P
Bauchat
Olivier
O
Le Marec
Julien
J
Chuquet
Laure
L
Guilhaudis
Jean A
JA
Boutin
Isabelle
I
Ségalas-Milazzo
Jean
J
Costentin
Hubert
H
Vaudry
Michèle
M
Baudy-Floc'h
David
D
Vaudry
Jérôme
J
Leprince
D000818:Animals; D001372:Aza Compounds / Q000494:pharmacology*; D002942:Circular Dichroism; D015195:Drug Design; D004355:Drug Stability; D005247:Feeding Behavior / Q000187:drug effects*; D006860:Hydrogen Bonding; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008970:Molecular Weight; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
D001372:Aza Compounds; D010455:Peptides; C476583:Qrfpr protein, mouse; D043562:Receptors, G-Protein-Coupled