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。该提案的具体目标是：1。目的：鉴定神经紧张素1受体（NTR1）的小分子激动剂。-采用高通量，高含量的初级分析，并使用各种二级分析确认命中。2. 通过目的1优化两到三种不同的先导化合物对NTR1激动剂的活性。该提案将确定新的小分子神经紧张素受体激动剂，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（国家药物滥用研究所研究报告系列，2006年）。我们建议使用基于细胞的初级试验，通过对大量化合物库的高含量筛选来鉴定新型小分子神经紧张素受体激动剂，并利用抑制绿色荧光蛋白报告蛋白的能力直接识别NTR1的激活状态。该发现项目中的铅优化NTR1激动剂将适用于旨在开发治疗安非他明滥用的新医学疗法的转化研究。

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.