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

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