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Rational Design of a Low Molecular Weight, Stable, Potent, and Long-Lasting GPR103 Aza-β3-pseudopeptide Agonist
- Source :
- Journal of Medicinal Chemistry, Journal of Medicinal Chemistry, 2012, 55 (17), pp.7516-7524. ⟨10.1021/jm300507d⟩, Journal of Medicinal Chemistry, American Chemical Society, 2012, 55 (17), pp.7516-7524. ⟨10.1021/jm300507d⟩
- Publication Year :
- 2012
- Publisher :
- American Chemical Society (ACS), 2012.
-
Abstract
- 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.
- Subjects :
- Male
Agonist
Long lasting
Intracerebroventricular injection
medicine.drug_class
Neuropeptide
MESH: Receptors, G-Protein-Coupled
MESH: Drug Design
Pharmacology
Receptors, G-Protein-Coupled
MESH: Circular Dichroism
Mice
03 medical and health sciences
0302 clinical medicine
Drug Stability
MESH: Drug Stability
Drug Discovery
medicine
Animals
MESH: Animals
MESH: Hydrogen Bonding
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM]
MESH: Mice
ComputingMilieux_MISCELLANEOUS
Injections, Intraventricular
030304 developmental biology
Orphan receptor
Aza Compounds
0303 health sciences
MESH: Peptides
Chemistry
Circular Dichroism
MESH: Molecular Weight
Rational design
Hydrogen Bonding
Feeding Behavior
MESH: Male
3. Good health
Molecular Weight
Drug Design
MESH: Aza Compounds
MESH: Feeding Behavior
Molecular Medicine
MESH: Injections, Intraventricular
Peptides
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 55
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....a94d5c8a5b5e442bb7e7c4049afd7859