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Oligopeptides as Neuropeptide Y Y4 Receptor Ligands: Identification of a High-Affinity Tetrapeptide Agonist and a Hexapeptide Antagonist
- Source :
- Journal of Medicinal Chemistry. 63:8198-8215
- Publication Year :
- 2020
- Publisher :
- American Chemical Society (ACS), 2020.
-
Abstract
- Within the family of neuropeptide Y (NPY) receptors, the Y4 receptor (Y4R) is unique as it prefers pancreatic polypeptide over NPY and peptide YY. Today, low-molecular-weight Y4R ligands are lacking, in particular antagonists. We synthesized a series of peptidic NPY Y4R ligands, derived from the hexapeptide acetyl-Arg-Tyr-Arg-Leu-Arg-Tyr-NH2 (1), reported to be a Y4R partial agonist with high affinity (pKi Y4R: 8.43). Peptide 1 was N-terminally extended as well as truncated and subjected to a d-amino acid scan, and Leu was replaced by different amino acids. Compounds were characterized by radioligand competition binding and functional studies (Cai2+ mobilization and β-arrestin 1/2 recruitment). N-terminal truncation of 1 resulted in a tetrapeptide (Arg-Leu-Arg-Tyr-NH2), being a Y4R partial agonist with unchanged Y4R affinity (pKi: 8.47). Remarkably, replacement of Leu in 1 and in derivatives of 1 by Trp turned Y4R agonism to antagonism, giving Y4R antagonists with pKi values ≤7.57.
- Subjects :
- Agonist
chemistry.chemical_classification
0303 health sciences
Tetrapeptide
Chemistry
Stereochemistry
medicine.drug_class
Peptide
Neuropeptide Y receptor
01 natural sciences
Partial agonist
0104 chemical sciences
010404 medicinal & biomolecular chemistry
03 medical and health sciences
Peptide YY
Drug Discovery
Radioligand
medicine
Molecular Medicine
Receptor
030304 developmental biology
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 63
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi...........183178c90b67c0e3e384c5f6012a9865