STRUCTURE-ACTIVITY RELATIONSHIP OF NOVEL PENTAPEPTIDE NEUROPEPTIDE-Y RECEPTOR ANTAGONISTS IS CONSISTENT WITH A NONCONTINUOUS EPITOPE FOR LIGAND-RECEPTOR BINDING

We report the first systematic study on short peptide structure affini ty and activity for the neuropeptide Y (NPY) receptor. A series of lin ear pentapeptides has been synthesized that display affinities in the low micromolar range toward rat brain NPY receptors. Furthermore, some of these compounds competitively antagonize the Y-1-type NPY receptor -mediated increase in cytosolic Ca2+ in human erythroleukemic (HEL) ce lls. The inactive NPY carboxyl-terminal pentapeptide (Thr-Arg-Gln-Arg- Tyr-NH2; IC50 > 100 mu M) was modified by replacing threonine with an aromatic amino acid and glutamine with leucine. This resulted in a ser ies of pentapepides with dramatically improved affinity (IC50 = 0.5-4 mu M) for the rat brain receptor. The structure-affinity data suggest that these peptides may represent a noncontinuous epitope containing t he amino-terminal tyrosine and the carboxyl-terminal residues Arg-35 a nd Tyr-36 of NPY.