Konieczny, Adam and Braun, Diana and Wifling, David and Bernhardt, Guenther and Keller, Max (2020) Oligopeptides as Neuropeptide Y Y-4 Receptor Ligands: Identification of a High-Affinity Tetrapeptide Agonist and a Hexapeptide Antagonist. JOURNAL OF MEDICINAL CHEMISTRY, 63 (15). pp. 8198-8215. ISSN 0022-2623, 1520-4804
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Within the family of neuropeptide Y (NPY) receptors, the Y-4 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 (pK(i) 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 (Ca-i(2+) mobilization and beta-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 (pK(i): 8.47). Remarkably, replacement of Leu in 1 and in derivatives of 1 by Trp turned Y4R agonism to antagonism, giving Y4R antagonists with pK(i) values <= 7.57.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PANCREATIC-POLYPEPTIDE; ALLOSTERIC SODIUM; AMINO ACIDS; FAMILY; DISCRIMINATION; REPLACEMENT; INHIBITION; EXPRESSION; ARGININE; CLONING; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 16 Mar 2021 08:27 |
| Last Modified: | 16 Mar 2021 08:27 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44023 |
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