Structure–Activity Relationships of a Series of Analogues of the RFamide-Related Peptide 26RFa
| Autor: | Le Marec, Olivier, Neveu, Cindy, Lefranc, Benjamin, Dubessy, Christophe, Boutin, Jean, Do-Régo, Jean, Costentin, Jean, Tonon, Marie-Christine, Tena-Sempere, Manuel, Vaudry, Hubert, Do-Régo, Jean, Leprince, Jérôme |
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| Přispěvatelé: | EPSM-Morbihan, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches Servier, Centre de Recherches de Croissy, Neuropsycho-pharmacologie expérimentale, Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Department of Cell Biology, Neuroendocrinologie cellulaire et moléculaire |
| Rok vydání: | 2011 |
| Předmět: |
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
MESH: Cricetinae Peptide MESH: Amino Acid Sequence MESH: Receptors G-Protein-Coupled [CHIM.THER]Chemical Sciences/Medicinal Chemistry Ligands MESH: Neuropeptides Receptors G-Protein-Coupled MESH: GTP-Binding Protein beta Subunits chemistry.chemical_compound MESH: Structure-Activity Relationship 0302 clinical medicine MESH: Cricetulus Cricetinae [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] Drug Discovery MESH: Ligands MESH: Animals Peptide sequence Alanine chemistry.chemical_classification 0303 health sciences GTP-Binding Protein beta Subunits Stereoisomerism Gonadotropin secretion Biochemistry MESH: Calcium Molecular Medicine Stereochemistry CHO Cells Transfection Structure-Activity Relationship 03 medical and health sciences Cricetulus MESH: CHO Cells Animals Structure–activity relationship Amino Acid Sequence 030304 developmental biology G protein-coupled receptor MESH: Transfection Neuropeptides Rational design MESH: Stereoisomerism chemistry [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology Calcium Norvaline 030217 neurology & neurosurgery |
| Zdroj: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, American Chemical Society, 2011, 54 (13), pp.4806-4814. ⟨10.1021/jm200418c⟩ |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm200418c |
| Popis: | International audience; 26RFa is a new member of the RFamide peptide family that has been identified as the endogenous ligand of the orphan GPCR GPR103. As the C-terminal heptapeptide (26RFa((20-26))) mimics the action of the native peptide on food intake and gonadotropin secretion in rodents, we have synthesized a series of analogues of 26RFa((20-26)) and measured their potency to induce [Ca(2+)](i) mobilization in Gα(16)-hGPR103-transfected CHO cells. Systematic replacement of each residue by an alanine (Ala scan) and its D-enantiomer (D scan) showed that the last three C-terminal residues were very sensitive to the substitutions while position 23 tolerated rather well both modifications. Most importantly, replacement of Ser(23) by a norvaline led to an analogue, [Nva(23)]26RFa((20-26)), that was 3-fold more potent than the native heptapeptide. These new pharmacological data, by providing the first information regarding the structure-activity relationships of 26RFa analogues, should prove useful for the rational design of potent GPR103 receptor ligands with potential therapeutic application. |
| Databáze: | OpenAIRE |
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