biostudies-literatureKuhn KKDeutsche Forschungsgemeinschaft3616-3631https://www.ebi.ac.uk/biostudies/studies/S-EPMC6044894biostudies-literatureUnknown2(7)The cross-linked pentapeptides (2<i>R</i>,7<i>R</i>)-diaminooctanedioyl-bis(Tyr-Arg-Leu-Arg-Tyr-amide) ((2<i>R</i>,7<i>R</i>)-BVD-74D, (2<i>R</i>,7<i>R</i>)-<b>1</b>) and octanedioyl-bis(Tyr-Arg-Leu-Arg-Tyr-amide) (<b>2</b>) as well as the pentapeptide Ac-Tyr-Arg-Leu-Arg-Tyr-amide (<b>3</b>) were previously described as neuropeptide Y Y₄ receptor (Y₄R) partial agonists. Here, we report on a series of analogues of (2<i>R</i>,7<i>R</i>)-<b>1</b> and <b>2</b> in which Arg², Leu³, or Arg⁴ were replaced by the respective aza-amino acids. The replacement of Arg² in <b>3</b> 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-<i>N</i>^ω-[(4-aminobutyl)aminocarbonyl]Arg-Leu-Arg-Tyr-amide (<b>35</b>), which was used as a precursor for a d-amino acid scan. The target compounds were investigated for Y₄R functional activity in assays with complementary readouts: aequorin Ca²⁺ and β-arrestin 1 or β-arrestin 2 assays. In contrast to the parent compounds, which are Y₄R agonists, several ligands were able to suppress the effect elicited by the endogenous ligand pancreatic polypeptide and therefore represent a novel class of peptide Y₄R antagonists.ACS omegaIn Search of NPY Y₄R Antagonists: Incorporation of Carbamoylated Arginine, Aza-Amino Acids, or d-Amino Acids into Oligopeptides Derived from the C-Termini of the Endogenous Agonists.PMC6044894GRK 1910KE 1857/1-1Littmann TBuschauer ADukorn SKuhn KKOzawa TTanaka MKeller MBernhardt GfalseIn Search of NPY Y₄R 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<i>R</i>,7<i>R</i>)-diaminooctanedioyl-bis(Tyr-Arg-Leu-Arg-Tyr-amide) ((2<i>R</i>,7<i>R</i>)-BVD-74D, (2<i>R</i>,7<i>R</i>)-<b>1</b>) and octanedioyl-bis(Tyr-Arg-Leu-Arg-Tyr-amide) (<b>2</b>) as well as the pentapeptide Ac-Tyr-Arg-Leu-Arg-Tyr-amide (<b>3</b>) were previously described as neuropeptide Y Y₄ receptor (Y₄R) partial agonists. Here, we report on a series of analogues of (2<i>R</i>,7<i>R</i>)-<b>1</b> and <b>2</b> in which Arg², Leu³, or Arg⁴ were replaced by the respective aza-amino acids. The replacement of Arg² in <b>3</b> 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-<i>N</i>^ω-[(4-aminobutyl)aminocarbonyl]Arg-Leu-Arg-Tyr-amide (<b>35</b>), which was used as a precursor for a d-amino acid scan. The target compounds were investigated for Y₄R functional activity in assays with complementary readouts: aequorin Ca²⁺ and β-arrestin 1 or β-arrestin 2 assays. In contrast to the parent compounds, which are Y₄R agonists, several ligands were able to suppress the effect elicited by the endogenous ligand pancreatic polypeptide and therefore represent a novel class of peptide Y₄R antagonists.2017-01-01T00:00:00Z2017 Jul2025-05-29T20:28:22.863Z2019-03-26T23:47:01ZS-EPMC60448943002369910.1021/acsomega.7b00451