Small Molecule Agonsists for the Neurotensin 1 Receptor

描述(由申请人提供)：本申请涉及国家药物滥用研究所(NIDA)感兴趣的一个重要领域：利用分子靶标治疗药物成瘾障碍。该提案的具体目的是：1.使用高通量、高含量的α-arrestin一次试验鉴定神经降压素1受体(NTR1)的小分子激动剂，并使用各种二次试验确认命中。2.通过目标1优化两到三种不同的先导化合物的NTR1激动剂活性。这项建议将鉴定新的小分子神经降压素受体激动剂，为开发治疗和预防甲基苯丙胺滥用的药物奠定基础。它解决了国家药物滥用研究所的一个直接目标，即需要新的方法来治疗甲基苯丙胺成瘾(NIDA研究报告系列，2006年)。我们建议通过使用基于细胞的初级实验对大量化合物进行高含量筛选来鉴定新的小分子神经降压素受体激动剂，并利用Arrestin-Green荧光蛋白报告程序直接识别NTR1的激活状态的能力。这一发现计划中的先导优化NTR1激动剂将适用于旨在开发治疗苯丙胺滥用的新医学疗法的转化性研究。 与公共健康相关：吸毒成瘾是美国的一个主要社会和经济问题。现在人们认为，药物滥用最好被归类为一种大脑疾病，因此应该接受药物治疗。苯丙胺衍生物，如甲基苯丙胺，是广泛滥用的药物，最近的证据表明，苯丙胺的使用可以被激活神经降压素受体的多肽激动剂抑制。这项建议的目标是确定小分子神经降压素受体激动剂。这些化合物将作为工具化合物用于研究药物寻找行为的途径，并可能为开发治疗苯丙胺滥用的新药物疗法提供基础。

DESCRIPTION (provided by applicant): This application addresses an important area of interest to the National Institute on Drug Abuse (NIDA): The utilization of molecular targets for the treatment of drug addiction disorders. The specific aims of the proposal are: 1. To identify small molecule agonists of the Neurotensin 1 Receptor (NTR1) using a ?-arrestin high throughput, high content primary assay, and confirming hits using a variety of secondary assays. 2. To optimize two to three distinct lead compounds for NTR1 agonist activity via aim 1. This proposal will identify novel small molecule neurotensin receptor agonists that form the foundation for developing drugs to treat and prevent methamphetamine abuse. It addresses an immediate goal of the National Institute on Drug Abuse that new approaches are needed for treating methamphetamine addiction (NIDA Research Report Series, 2006). We propose to identify novel small molecule neurotensin receptor agonists by high content screening of large libraries of compounds using a primary assay that is cell based and exploit the ability of an arrestin-green fluorescent protein reporter to directly recognize the activated state of the NTR1. Lead optimized NTR1 agonists from within this discovery program will be applicable for translational studies aimed towards the development of novel medical therapies to treat amphetamine abuse. PUBLIC HEALTH RELEVANCE: Drug addiction is a major social and economic problem for the US. It is now believed that drug abuse is best classified as a disorder of the brain, and as such should be amenable to medical therapy. Amphetamine derivatives like methamphetamine are widely abused drugs and recent evidence indicates that amphetamine use can be suppressed by peptide agonists that activate neurotensin receptors. The goal of this proposal is to identify small molecule neurotensin receptor agonists. These compounds will be used as tool compounds to study the pathways involved in drug seeking behaviors and may provide the basis to develop novel drug therapies to treat amphetamine abuse.