GR231118 (1229U91) and other analogues of the C-terminus of neuropeptide Y are potent neuropeptide Y Y1 receptor antagonists and neuropeptide Y Y4 receptor agonists.

Abstract

GR231118, BW1911U90, Bis(31/31')[[Cys31, Trp32, Nva34] neuropeptide Y(31-36)] (T-190) and [Trp-Arg-Nva-Arg-Tyr]2-NH2 (T-241) are peptide analogs of the C-terminus of neuropeptide Y that have recently been shown to be antagonists of the neuropeptide Y Y1 receptor. In this study, the activity of these peptides at each of the cloned neuropeptide Y receptor subtypes is determined in radioligand binding assays and in functional assays (inhibition of forskolin-stimulated cAMP formation). GR231118 is a potent antagonist at the human and rat neuropeptide Y Y1 receptors (pA2 = 10.5 and 10.0, respectively; pKi = 10.2 and 10.4, respectively), a potent agonist at the human neuropeptide Y Y4 receptor (pEC50 = 8.6; pKi = 9.6) and a weak agonist at the human and rat neuropeptide Y Y2 and Y5 receptors. GR231118 also has high affinity for the mouse neuropeptide Y Y6 receptor (pKi = 8.8). Therefore, GR231118 is a relatively selective neuropeptide Y Y1 receptor antagonist, but has appreciable activity at the neuropeptide Y Y4 and Y6 receptors as well. BW1911U90, T-190 and T-241 are moderately potent neuropeptide Y Y1 receptor antagonists (pA2 = 7.1, 5.8 and 6.5, respectively; pKi = 8.3, 6.5 and 6.8, respectively) and neuropeptide Y Y4 receptor agonists (pEC50 = 6.8, 6.3 and 6.6, respectively; pKi; 8.3, 7.7 and 8.3, respectively). These data suggest that the C-terminus of neuropeptide Y and related peptides is sufficient for activation of the neuropeptide Y Y4 receptor, but is not sufficient for activation of the neuropeptide Y Y1 receptor. Because BW1911U90, T-190 and T-241 are significantly less potent at the cloned human neuropeptide Y Y1 receptor than at the neuropeptide Y receptor in human erythroleukemia cells, these cells may express a novel neuropeptide Y receptor with high affinity for these peptides.

• Authors: E M Parker, C K Babij, A Balasubramaniam, R E Burrier, M Guzzi, F Hamud, G Mukhopadhyay, M S Rudinski, Z Tao, M Tice, L Xia, D E Mullins, B G Salisbury
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 349 Issue 1 Pg. 97-105 (May 15 1998) ISSN: 0014-2999 [Print] Netherlands
• PMID: 9669502 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 1229U91
• BW 1991U90
• Neuropeptide Y
• Oligopeptides
• Peptides, Cyclic
• Receptors, Neuropeptide Y
• T 241
• neuropeptide Y (31-36), bis(31-31')(Cys(31)-Trp(32)-Nva(34))
• neuropeptide Y-Y1 receptor
• neuropeptide Y4 receptor

Topics

• Amino Acid Sequence
• Animals
• CHO Cells
• COS Cells
• Cricetinae
• Humans
• Mice
• Molecular Sequence Data
• Neuropeptide Y (analogs & derivatives, chemistry, metabolism, pharmacology)
• Oligopeptides (chemistry, pharmacology)
• Peptides, Cyclic (chemistry, pharmacology)
• Radioligand Assay
• Rats
• Receptors, Neuropeptide Y (agonists, antagonists & inhibitors, biosynthesis)
• Transfection