Oligopeptides as Neuropeptide Y Y Receptor Ligands: Identification of a High-Affinity Tetrapeptide Agonist and a Hexapeptide Antagonist.

Within the family of neuropeptide Y (NPY) receptors, the Y receptor (YR) is unique as it prefers pancreatic polypeptide over NPY and peptide YY. Today, low-molecular-weight YR ligands are lacking, in particular antagonists. We synthesized a series of peptidic NPY YR ligands, derived from the hexapeptide acetyl-Arg-Tyr-Arg-Leu-Arg-Tyr-NH (), reported to be a YR partial agonist with high affinity (p YR: 8.43). Peptide 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 mobilization and β-arrestin 1/2 recruitment). N-terminal truncation of resulted in a tetrapeptide (Arg-Leu-Arg-Tyr-NH), being a YR partial agonist with unchanged YR affinity (p: 8.47). Remarkably, replacement of Leu in and in derivatives of by Trp turned YR agonism to antagonism, giving YR antagonists with p values ≤7.57.