Development of a High Throughput Screening Galanin 3 Receptor Assay

描述(由申请人提供)：本检测开发提案的主要目的是在为Galanin 3受体寻找小分子药理工具这一目标的全面整合努力中提供关键一步。斯克里普斯研究所(TSRI)是化学和生物学领域的卓越中心，其研究人员在识别和表征小分子药理工具方面有着良好的成功记录。斯克里普斯分子图书馆筛选中心(MLSC)正在积极支持NIH路线图寻找有用的分子工具的努力。为了创造极好的小分子发现机会，最终通过X01应用机制提交给MLSC网络，我们希望为临床重要的神经科学靶点增强关键的基本受体工具，并为该系统的高通量生物学做好准备。1.建立了用于高通量筛选的GALR3β-内酰胺酶报告试剂盒和计数器筛查方法。2.建立和验证HTS 3的GALR3拮抗剂实验。明确HTS衍生化合物导联的体外和体内评价途径。Galanin是一种具有三个GPCRs(GALR1-3)的神经肽，介导其在脑和外周神经系统的作用。GALR3是抗抑郁药物作用的新靶点，医学上迫切需要具有新作用机制的抗抑郁药物。需要有效的、特定的和生物可用的GALR3拮抗剂来进一步验证这一治疗焦虑和抑郁的靶点。具有所需的高效、选择性和跨越血脑屏障(BBB)能力的化合物将在焦虑和抑郁的动物模型中进行评估。对Galanin受体激动剂和拮抗剂的概念验证(POC)研究可能最终导致几种神经疾病的治疗方式得到改进。

DESCRIPTION (provided by applicant): The major purpose of this Assay Development Proposal is to provide a key step in a fully integrated effort towards the goal of finding small molecule pharmacological tools for the Galanin 3 Receptor. The Scripps Research Institute (TSRI) is a center of excellence in chemistry and biology and its investigators have a strong record of success in identifying and characterizing small molecule pharmacological tools. The Scripps Molecular Libraries Screening Center (MLSC) is taking an active role supporting the NIH Roadmap's effort to identify useful molecular tools. To create excellent small molecule discovery opportunities for eventual submission to the MLSC Network through the X01 application mechanism, we would like to enhance critical basic receptor tools for a clinically important neuroscience target, and ready this system for high throughput biology. 1. Develop a GALR3 beta-lactamase reporter assay and counter screens for high throughput screening. 2. Format and validate the GALR3 antagonist assay for HTS 3. Define the pathway for evaluating HTS derived compound leads in vitro and in vivo Galanin is a neuropeptide with three GPCRs (GALR1-3) that mediates its effects in the brain and peripheral nervous system. GALR3 represents a novel target for antidepressant drug action and there is a great medical need for antidepressants with new mechanism of action. Potent, specific and bioavailable GALR3 antagonists are needed to further validate this target for the treatment of anxiety and depression. Compounds with the desired profile of high potency, selectivity and ability to cross the blood-brain barrier (BBB) will be evaluated in animal models of anxiety and depression. Proof of concept (POC) studies with Galanin receptor agonists and antagonists may ultimately lead to improved therapeutic modalities for several neurological diseases.