Parker E M, Babij C K, Balasubramaniam A, Burrier R E, Guzzi M, Hamud F, Mukhopadhyay G, Rudinski M S, Tao Z, Tice M, Xia L, Mullins D E, Salisbury B G
Department of Central Nervous System and Cardiovascular Research, Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA.
Eur J Pharmacol. 1998 May 15;349(1):97-105. doi: 10.1016/s0014-2999(98)00171-x.
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.
GR231118、BW1911U90、双(31/31')[[半胱氨酸31、色氨酸32、正缬氨酸34]神经肽Y(31 - 36)](T - 190)和[色氨酸 - 精氨酸 - 正缬氨酸 - 精氨酸 - 酪氨酸]2 - NH2(T - 241)是神经肽Y C末端的肽类似物，最近已被证明是神经肽Y Y1受体的拮抗剂。在本研究中，通过放射性配体结合试验和功能试验(抑制福斯高林刺激的环磷酸腺苷形成)测定了这些肽在每种克隆的神经肽Y受体亚型上的活性。GR231118是人和大鼠神经肽Y Y1受体的强效拮抗剂(分别为pA2 = 10.5和10.0；pKi分别为10.2和10.4)，是人神经肽Y Y4受体的强效激动剂(pEC50 = 8.6；pKi = 9.6)，也是人和大鼠神经肽Y Y2和Y5受体的弱激动剂。GR231118对小鼠神经肽Y Y6受体也具有高亲和力(pKi = 8.8)。因此，GR231118是一种相对选择性的神经肽Y Y1受体拮抗剂，但在神经肽Y Y4和Y6受体上也具有明显活性。BW1911U90、T - 190和T - 241是中等效力的神经肽Y Y1受体拮抗剂(分别为pA2 = 7.1、5.8和6.5；pKi分别为8.3、6.5和6.8)和神经肽Y Y4受体激动剂(分别为pEC50 = 6.8、6.3和6.6；pKi分别为8.3、7.7和8.3)。这些数据表明神经肽Y的C末端及相关肽足以激活神经肽Y Y4受体，但不足以激活神经肽Y Y1受体。由于BW1911U90、T - 190和T - 241在克隆的人神经肽Y Y1受体上的效力明显低于在人红白血病细胞中的神经肽Y受体，这些细胞可能表达一种对这些肽具有高亲和力的新型神经肽Y受体。
