Development of Chemical Probes to Investigate the Role of NTSR1 in CNS Disorders

开发化学探针来研究 NTSR1 在中枢神经系统疾病中的作用

基本信息

批准号：
8082595
负责人：
Patricia Helen McDonald
金额：
$ 42.4万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8082595
关键词：
Academia Agonist Animal Model Attention Automobile Driving Biological Assay Brain Cells Central Nervous System Diseases Chemicals Coupled DA10 Development Dopamine Drug Addiction Drug Industry Drug Kinetics Evaluation Fingerprint Florida Funding Opportunities Future G alpha q Protein GTP-Binding Proteins Goals In Vitro Lead Ligands Literature Methods Microsomes Monitor Morphologic artifacts National Institute of Drug Abuse Neurotensin Peptides Pharmaceutical Chemistry Phase Physiological Property Resources Rodent Role Screening procedure Series Signal Transduction Signal Transduction Pathway Structure System Work analog base cell type cheminformatics counterscreen design drug metabolism high throughput screening in vitro Assay in vivo meetings new technology novel programs public health relevance receptor response small molecule transmission process

项目摘要

DESCRIPTION (provided by applicant): The neurotensin system has attracted a lot of attention as a potential target to treat drug addiction due to its ability to modulate dopamine signaling and transmission. However, despite extensive effort by the pharmaceutical industry and academia over the past 30 years, there are still no potent, selective NTSR1 non- peptide agonists or potentiators and only a few antagonists described in the literature. From a high throughput screening (HTS) perspective most of the attention has been paid to interactions between the NTSR1 receptor and its signaling through the Gq protein-coupled signal transduction pathway. However, it is now clear that NTSR1 can couple to multiple G proteins and may even signal in a G-protein independent fashion. Hence, the overall goal of this proposal is to employ a multiple assay approach to drive an iterative medicinal chemistry program aimed at identifying potent, selective, cell penetrant positive modulators of NTSR1. To avoid missing potential valuable compounds our approach is to screen compounds in multiple cell-based assays with different functional readouts. This can be viewed as casting a wide net to capture compounds that modulate the receptor via different mechanisms and then letting the efficacy in the functional assays enable us to create a cellular response profile or 'functional fingerprint' for each compound. This in vitro functional fingerprint will be invaluable for future evaluation of compounds in vivo, the challenge being to identify physiological consequences of functional selectivity at NTSR1. Thus, our multiple assay approach is a vast improvement over the single [Ca2+]/FLIPR assay approach typically pursued by the pharmaceutical industry. PUBLIC HEALTH RELEVANCE: The neurotensin 1 receptor (NTSR1) is expressed peripherally and in the CNS and has attracted a lot of attention as a potential target to treat drug addiction due to its ability to modulate dopamine signaling and transmission. This proposal seeks to develop a series of cell-based functional assays to drive an iterative medicinal chemistry program aimed at identifying potent, selective, cell penetrant positive modulators of NTSR1.

描述（由申请人提供）：神经素系统由于能够调节多巴胺信号传导和传播的能力而引起了很多关注，作为治疗药物成瘾的潜在目标。然而，尽管制药行业和学术界在过去30年中进行了广泛的努力，但仍然没有有效的，有选择性的NTSR1非肽激动剂或增强剂，也没有文献中描述的少数拮抗剂。从高吞吐量筛选（HTS）的角度来看，大多数注意力都用于通过GQ蛋白偶联的信号转导途径之间的NTSR1受体及其信号传导之间的相互作用。但是，现在很明显，NTSR1可以将其与多种G蛋白息息，甚至可以以G蛋白独立的方式发出信号。因此，该提案的总体目标是采用多种测定方法来推动迭代药物化学计划，旨在识别NTSR1的有效，选择性的细胞渗透阳性调节剂。为避免缺少潜在的有价值的化合物，我们的方法是在具有不同功能读数的多个基于单元的测定中筛选化合物。这可以看作是铸造宽网量以捕获通过不同机制调节受体的化合物，然后在功能测定中允许的功效使我们能够为每种化合物创建一个细胞响应曲线或“功能性指纹”。这种体外功能指纹对于体内化合物的将来评估是无价的，这是确定NTSR1功能选择性的生理后果的挑战。因此，我们的多种测定方法是对制药行业通常采用的单个[CA2+]/FLIPR测定方法的巨大改进。公共卫生相关性：神经素1受体（NTSR1）在外围和中枢神经系统中表达，并且由于其调节多巴胺信号传导和传播的能力而引起了很多关注，作为治疗药物成瘾的潜在目标。该建议旨在开发一系列基于细胞的功能测定，以推动迭代药物化学计划，以识别NTSR1的有效，选择性的细胞渗透阳性调节剂。