N-Terminus to Arginine Side-Chain Cyclization of Linear Peptidic Neuropeptide Y Y₄ Receptor Ligands Results in Picomolar Binding Constants

Abstract

The family of neuropeptide Y (NPY) receptors comprises four subtypes (Y₁R, Y₂R, Y₄R, Y₅R), which are addressed by at least three endogenous peptides, i.e., NPY, peptide YY, and pancreatic polypeptide (PP), the latter showing a preference for Y₄R. A series of cyclic oligopeptidic Y₄R ligands were prepared by applying a novel approach, i.e., N-terminus to arginine side-chain cyclization. Most peptides acted as Y₄R partial agonists, showing up to 60-fold higher Y₄R affinity compared to the linear precursor peptides. Two cyclic hexapeptides (<b>18</b>, <b>24</b>) showed higher Y₄R potency (Ca²⁺ aequorin assay) and, with p<i>K</i>_i values >10, also higher Y₄R affinity compared to human pancreatic polypeptide (hPP). Compounds such as <b>18</b> and <b>24</b>, exhibiting considerably lower molecular weight and considerably more pronounced Y₄R selectivity than PP and previously described dimeric peptidic ligands with high Y₄R affinity, represent promising leads for the preparation of labeled tool compounds and might support the development of drug-like Y₄R ligands.