Selective and Brain Penetrant Neuropeptide Y Y2 Receptor Antagonists Discovered by Whole-Cell High-Throughput Screening
Selective and Brain Penetrant Neuropeptide Y Y2 Receptor Antagonists Discovered by Whole-Cell High-Throughput Screening
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DOI：
10.1124/mol.109.058677
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发表时间：
2010-01-01
影响因子：
3.6
通讯作者：
Hodder, Peter S.
中科院分区：
文献类型：
--
作者：
Brothers, Shaun P.;Saldanha, S. Adrian;Hodder, Peter S.
神经肽Y Y2受体（Y2 R）在人类疾病如肥胖、情绪障碍和酒精中毒中的作用可以通过使用与目前可用的Y2 R拮抗剂N-[（1 S）-4-[（1（氨基亚氨基甲基）氨基]-1-[2-（3，5-二氧代-1，2-二苯基-1，2，4-三唑烷-4-基）乙基]氨基]羰基]丁基]-1-[2-[4-（6，11-二氢-6-氧代-5H-二苯并[B，e]氮杂卓-11-基）-1-哌嗪基]-2-氧代乙基]-环戊烷乙酰胺）（BIIE 0246）。这里提出了五个有效的，选择性的，公开可用的Y2 R拮抗剂确定的高通量筛选方法。这些化合物属于四种化学支架，在结构上与拟肽BIIE 0246不同。在功能试验中，测得对Y2 R的IC 50值在199和4400 nM之间，对相关的NPY-Y1受体（Y1 R）没有明显的活性。化合物还以高亲和力（Ki值在1.55和60 nM之间）从Y2 R置换放射性标记的肽YY，而不从Y1 R置换相同的配体。与BIIE 0246相反，用NPY进行的Schild分析表明，五种化合物中有两种表现为竞争性拮抗剂。对中枢神经系统中发现的40种受体、离子通道和转运蛋白的分析表明，5种Y2 R拮抗剂表现出比BIIE 0246更大的选择性。此外，这些拮抗剂穿透血脑屏障的能力使它们更适合于脑和外周中Y2 R功能的药理学研究。
The role of neuropeptide Y Y2 receptor (Y2R) in human diseases such as obesity, mood disorders, and alcoholism could be better resolved by the use of small-molecule chemical probes that are substantially different from the currently available Y2R antagonist, N-[(1S)-4-[(aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-Yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide) (BIIE0246). Presented here are five potent, selective, and publicly available Y2R antagonists identified by a high-throughput screening approach. These compounds belong to four chemical scaffolds that are structurally distinct from the peptidomimetic BIIE0246. In functional assays, IC50 values between 199 and 4400 nM against the Y2R were measured, with no appreciable activity against the related NPY-Y1 receptor (Y1R). Compounds also displaced radiolabeled peptide YY from the Y2R with high affinity (K-i values between 1.55 and 60 nM) while not displacing the same ligand from the Y1R. In contrast to BIIE0246, Schild analysis with NPY suggests that two of the five compounds behave as competitive antagonists. Profiling against a panel of 40 receptors, ion channels, and transporters found in the central nervous system showed that the five Y2R antagonists demonstrate greater selectivity than BIIE0246. Furthermore, the ability of these antagonists to penetrate the blood-brain barrier makes them better suited for pharmacological studies of Y2R function in both the brain and periphery.