Structure-activity relationship of novel pentapeptide neuropeptide y receptor antagonists is consistent with a noncontinuous epitope for ligand-receptor binding
Daniels, A.J.; Matthews, J.E.; Viveros, O.H.; Leban, J.J.; Cory, M.; Heyer, D.
Molecular Pharmacology 48(3): 425-432
1995
ISSN/ISBN: 0026-895X PMID: 7565622 Document Number: 446724
We report the first systematic study on short peptide structure affinity and activity for the neuropeptide Y (NPY) receptor. A series of linear 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 Y1-type NPY receptor-mediated increase in cytosolic Ca2+ in human erythroleukemic (HEL) cells. The inactive NPY carboxyl-terminal pentapeptide (Thr-Arg-Gln-Arg-Tyr-NH2; IC50 > 100 microM) was modified by replacing threonine with an aromatic amino acid and glutamine with leucine. This resulted in a series of pentapeptides with dramatically improved affinity (IC50 = 0.5-4 microM) for the rat brain receptor. The structure-affinity data suggest that these peptides may represent a noncontinuous epitope containing the amino-terminal tyrosine and the carboxyl-terminal residues Arg-35 and Tyr-36 of NPY.