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 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.
Daniels
A J
AJ
Division of Pharmacology, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709, USA.
Matthews
J E
JE
Viveros
O H
OH
Leban
J J
JJ
Cory
M
M
Heyer
D
D
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D000939:Epitopes / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism; D008024:Ligands; D008297:Male; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000378:metabolism; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium; D014407:Tumor Cells, Cultured
D000939:Epitopes; D008024:Ligands; D009478:Neuropeptide Y; D010455:Peptides; D017476:Receptors, Neuropeptide Y; D014316:Tritium; D002118:Calcium