Pharmacological characterization of <SUP>125</SUP>I-1229U91 binding to Y1 and Y4 neuropeptide Y/peptide YY receptors

作     者：Schober, DA Gackenheimer, SL Heiman, ML Gehlert, DR 

作者机构：Eli Lilly & Co Lilly Corp Ctr Lilly Res Labs Lilly Neurosci Indianapolis IN 46285 USA Eli Lilly & Co Lilly Corp Ctr Lilly Res Labs Lilly Endocrine Res Indianapolis IN 46285 USA 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：2000年第293卷第1期

页      面：275-280页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

主　　题：放射自显影术 结合 竞争性/药物作用 脑化学/药物作用 CHO细胞 克隆 分子 仓鼠亚科 碘放射性同位素/诊断应用 动力学 膜/药物作用 膜/代谢 神经肽Y/拮抗剂和抑制剂 神经肽Y/代谢 神经肽类/拮抗剂和抑制剂 胰多肽/代谢 肽类 环/药代动力学 大鼠 Sprague-Dawley 受体 神经肽Y/拮抗剂和抑制剂 受体 神经肽Y/代谢 动物 人类 男(雄)性 大鼠 

摘      要：1229U91 (GW1229 or GR231118) [IIe,Glu,Pro,Dpr,Tyr, Arg,Leu,Arg,Tyr-NH2)2 cyclic (2,4 ),(2 4)-diamide] has been reported by several research groups to be a potent antagonist at the Y1 neuropeptide Y (NPY) receptor subtype. However, 1229U91 also displaces I-125-peptide YY (PYY) with high affinity from the Y4 subtype. Previously, we reported that 1229U91 had full agonist properties for the Y4 receptor. To characterize the pharmacological properties of 1229U91 directly, we had it radioiodinated with the chloromine-T method. I-125-1229U91 bound to cell lines expressing the human Y1 and Y4 receptors with high affinity. The K-d and B-max for I-125-1229U91 binding to Y1 were 14.9 pM and 1458 fmol/mg protein, respectively. The Y4 receptor bound I-125-1229U91 with a K-d of 12.5 pM and a B-max of 1442 fmol/mg protein. When competing I-125-1229U91 binding from Y1 and Y4 receptors, a similar rank order of potency was observed: 1229U91 [Leu(31),pro(34)]-NPY greater than or equal to [Leu(31),pro(34)]-PYY PYY greater than or equal to NPY NPY(2-36) PYY(3-36). Pancreatic polypeptide (PP) potently displaced I-125-1229U91 from the Y4 receptor, but displayed little affinity for Y1. In autoradiographic studies with rat brain sections, I-125-1229U91 bound with a distribution similar to that reported for the Y1 receptor when localized with I-125-[Leu(31),Pro(34)]-PYY. Brain regions exhibiting binding sites for I-125-PP were not detected with this radioligand. Those include the interpeduncular nucleus and the periventricular nucleus of the hypothalamus. Furthermore, I-125-labeled rat PP was not displaced from these areas with 10 nM 1229U91. Thus, I-125-1229U91 is a high affinity Y1 and Y4 radioligand and binds with a distribution in the rat brain consistent with the localization of the Y1 receptor.