Discovery of Small-Molecule Modulators of the Human Y4 Receptor.
Discovery of Small-Molecule Modulators of the Human Y4 Receptor.
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DOI：
10.1371/journal.pone.0157146
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Meiler J
中科院分区：
文献类型：
--
作者：
Sliwoski G;Schubert M;Stichel J;Weaver D;Beck-Sickinger AG;Meiler J
人神经肽Y 4受体（Y 4 R）及其天然配体胰多肽通过发出饱腹感信号和调节食物摄入以及增加能量消耗来关键地参与人体代谢的调节。因此，该受体代表了治疗肥胖症的假定靶标。关于治疗复杂代谢紊乱的新方法，特别是在多受体系统中，小分子变构调节剂在过去几年中一直是研究的焦点。然而，迄今为止还没有描述Y 4 R的正变构调节剂或激动剂。在这项研究中，通过高通量筛选鉴定了来自氯硝柳胺支架的小分子化合物，以增加Y 4 R活性。表征化合物的效力及其对人Y 4 R的作用以及对Y1 R、Y2 R和Y 5 R的选择性。这些化合物提供了围绕这种常见支架的结构-活性关系概况，并为Y 4 R的正变构调节剂的命中-先导优化和表征奠定了基础。
The human neuropeptide Y4 receptor (Y4R) and its native ligand, pancreatic polypeptide, are critically involved in the regulation of human metabolism by signaling satiety and regulating food intake, as well as increasing energy expenditure. Thus, this receptor represents a putative target for treatment of obesity. With respect to new approaches to treat complex metabolic disorders, especially in multi-receptor systems, small molecule allosteric modulators have been in the focus of research in the last years. However, no positive allosteric modulators or agonists of the Y4R have been described so far. In this study, small molecule compounds derived from the Niclosamide scaffold were identified by high-throughput screening to increase Y4R activity. Compounds were characterized for their potency and their effects at the human Y4R and as well as their selectivity towards Y1R, Y2R and Y5R. These compounds provide a structure-activity relationship profile around this common scaffold and lay the groundwork for hit-to-lead optimization and characterization of positive allosteric modulators of the Y4R.