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

高通量筛选发现孤儿 GPCR GPR151 的小分子调节剂

基本信息

批准号：
9191286
负责人：
Thomas D Bannister
金额：
$ 87.1万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9191286
关键词：
Address Affect Agonist Behavior Bilateral Biological Assay Biological Process Biosensor Brain Brain region Cell Line Cells Central Nervous System Diseases Chemicals Chemistry Cherry - dietary Cognitive Complex Corpus striatum structure Cyclic AMP Detection Discrimination Disease Drug Addiction Drug Targeting Dyes Emotional Enzymes Evaluation Family Functional disorder G-Protein-Coupled Receptors GTP-Binding Proteins Habenula Heterotrimeric GTP-Binding Proteins Image In Situ Hybridization Label Lead Ligands Measurement Measures Membrane Potentials Mental Depression Messenger RNA Miniaturization Molecular Probes Monitor Neurons Orphan Pattern Pharmacology Pharmacotherapy Physiological Physiological Processes Play Preparation Prosencephalon Rattus Reader Receptor Activation Rhodopsin Role Scheme Schizophrenia Second Messenger Systems Sequence Homology Series Signal Transduction Signal Transduction Pathway Structure Structure-Activity Relationship System Technology Therapeutic Triage abstracting analog base bone counterscreen cyclic-nucleotide gated ion channels electric impedance emotion regulation galanin receptor high throughput screening in vivo innovation miniaturize neuropsychiatric disorder new therapeutic target novel overexpression receptor response screening second messenger small molecule small molecule libraries success tool trafficking

项目摘要

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.

项目总结/摘要孤儿G蛋白偶联受体GPR 151在哺乳动物脑中具有独特的分布模式，高度特异性地富集在被称为缰核复合体的小的双侧脑结构中。这结构发送投射到多巴胺能纹状体并接收来自边缘前脑的输入，调节这些大脑区域之间的交流。因此，无论是在解剖学上还是功能上，调节情感、动机和认知行为。因此，据信，缰在神经精神疾病的病理生理学中起着至关重要的作用，精神分裂症、抑郁症和药物依赖。受限制的和独特的大脑表达模式， GPR 151表明该受体在调节缰核复合体中的作用，从而影响这种作用。紊乱在本提案中，我们将实施和验证一种HTS相容的基于细胞的功能测定，有助于鉴定有效的GPR 151选择性小分子分子探针。这些分子将然后优化并用于询问GPR 151在调节缰核复合体中的作用以及 GPR 151对正常生理过程和疾病状态的调节。