In Search of NPY YR Antagonists: Incorporation of Carbamoylated Arginine, Aza-Amino Acids, or d-Amino Acids into Oligopeptides Derived from the C-Termini of the Endogenous Agonists.

The cross-linked pentapeptides (2,7)-diaminooctanedioyl-bis(Tyr-Arg-Leu-Arg-Tyr-amide) ((2,7)-BVD-74D, (2,7)-) and octanedioyl-bis(Tyr-Arg-Leu-Arg-Tyr-amide) () as well as the pentapeptide Ac-Tyr-Arg-Leu-Arg-Tyr-amide () were previously described as neuropeptide Y Y receptor (YR) partial agonists. Here, we report on a series of analogues of (2,7)- and in which Arg, Leu, or Arg were replaced by the respective aza-amino acids. The replacement of Arg in with a carbamoylated arginine building block and the extension of the N-terminus by an additional arginine led to the high-affinity hexapeptide Ac-Arg-Tyr--[(4-aminobutyl)aminocarbonyl]Arg-Leu-Arg-Tyr-amide (), which was used as a precursor for a d-amino acid scan. The target compounds were investigated for YR functional activity in assays with complementary readouts: aequorin Ca and β-arrestin 1 or β-arrestin 2 assays. In contrast to the parent compounds, which are YR agonists, several ligands were able to suppress the effect elicited by the endogenous ligand pancreatic polypeptide and therefore represent a novel class of peptide YR antagonists.