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

GR231118, BW1911U90, Bis(31/31'){[Cys(31), Trp(32), Nva(34)] 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 Y-1 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 Y-1 receptors (pA(2) = 10.5 and 10.0, respectively; pK(i) = 10.2 and 10.4, respectively), a potent agonist at the human neuropeptide Y Y-4 receptor (pEC(50) = 8.6; pK(i) = 9.6) and a weak agonist at the human and rat neuropeptide Y Y-2 and Y-5 receptors. GR231118 also has high affinity for the mouse neuropeptide Y Y-6 receptor (pK(i) = 8.8). Therefore, GR231118 is a relatively selective neuropeptide Y Y-1 receptor antagonist, but has appreciable activity at the neuropeptide Y Y-4 and Y-6 receptors as well. BW1911U90, T-190 and T-241 are moderately potent neuropeptide Y Y-1 receptor antagonists (pA(2) = 7.1, 5.8 and 6.5, respectively; pK(i) = 8.3, 6.5 and 6.8, respectively) and neuropeptide Y Y-4 receptor agonists (pEC(50) = 6.8, 6.3 and 6.6, respectively; pK(i);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 Y(1 )receptor, but is not sufficient for activation of the neuropeptide Y Y-1 receptor. Because BW1911U90, T-190 and T-241 are significantly less potent at the cloned human neuropeptide Y Y-1 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. (C) 1998 Elsevier Science B.V. All rights reserved.