High Throughput Screening to Discover Small Molecule Modulators of the Orphan GPCR GPR151

项目摘要/摘要 孤儿G蛋白偶联受体GPR151在哺乳动物大脑中有独特的分布模式， 在一个称为缰核复合体的小的双侧脑结构中具有高度特异性的丰富。这 结构向多巴胺能纹状体发送投射，并接受边缘前脑的输入， 调节这些大脑区域之间的串扰。因此，它的位置非常理想，从解剖学和 在功能上，调节情绪、动机和认知行为。因此，人们相信 缰核在神经精神障碍的病理生理学中起着至关重要的作用，如 精神分裂症、抑郁症和药物依赖。限制和独特的脑表达模式 GPR151提示该受体在调节缰核复合体中发挥作用，从而影响 精神错乱。在这项建议中，我们将实现和微型化HTS兼容的基于细胞的功能分析，以 便于鉴定有效的GPR151选择性小分子探针。这些分子将 然后被优化并用来询问GPR151‘S在调节缰核复合体中的作用和对其的影响 GPR151对正常生理过程和疾病状态均有调节作用。

Project Summary/Abstract The orphan G protein-coupled receptor GPR151 has a distinctive distribution pattern in mammalian brains, with highly specific enrichment in a small bilateral brain structure known as the habenula complex. This structure sends projections to the dopaminergic striatum and receives inputs from the limbic forebrain, modulating cross-talk between these brain regions. It is therefore ideally located, both anatomically and functionally, to regulate emotional, motivational and cognitive behaviors. Consequently, it is believed that the habenula plays a critically important role in the pathophysiology of neuropsychiatric disorders such as schizophrenia, depression and drug dependence. The restricted and unique brain expression pattern of GPR151 suggests a role for this receptor in regulating the habenula complex and thus affecting such disorders. In this proposal we will implement and miniaturize a HTS-compatible cell-based functional assay to facilitate the identification of potent GPR151-selective small molecule molecular probes. These molecules will then be optimized and used to interrogate GPR151's role in regulating the habenula complex and the impact of GPR151 modulation upon both normal physiological processes and disease states.