Small Molecule Agonsists for the Neurotensin 1 Receptor

神经降压素 1 受体的小分子激动剂

基本信息

批准号：
7845378
负责人：
LAWRENCE S. BARAK
金额：
$ 3.9万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-04 至 2011-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7845378
关键词：
Addictive Behavior Address Agonist Alkaloids Amphetamine Abuse Amphetamines Area Arrestins Behavior Biological Assay Brain Brain Diseases Cells Central Nervous System Diseases Cognitive deficits Crime Data Development Disease Dopamine Drug Addiction Drug abuse Economics Ephedra Epidemic Foundations Funding Goals Green Fluorescent Proteins Hyperactive behavior Individual Lead Learning Libraries Medical Methamphetamine Methamphetamine dependence Molecular Target National Institute of Drug Abuse Neuraxis Neurotensin Neurotensin Receptors Pathway interactions Peptides Pharmaceutical Preparations Pharmacology Pharmacotherapy Productivity Regulatory Pathway Relapse Reporter Reporting Research Screening procedure Series United States addiction base drug of abuse drug seeking behavior ecstasy interest methamphetamine abuse neurotoxicity novel novel strategies prevent programs psychostimulant public health relevance receptor reward processing scaffold small molecule social tool translational study transmission process

项目摘要

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.

描述（由申请人提供）：本申请介绍了美国国家药物滥用研究所（NIDA）的重要领域：分子靶标用于治疗药物成瘾障碍的重要领域。该提案的具体目的是：1。使用？ - arrestin高吞吐量，高含量主要测定法，并使用多种次级测定法确认命中率。 2。通过AIM 1优化NTR1激动剂活性的两到三种不同的铅化合物。该建议将确定新型的小分子神经素受体受体激动剂，构成了为治疗和预防甲基苯丙胺滥用的药物的基础。它解决了国家药物滥用研究所的直接目标，即治疗甲基苯丙胺成瘾需要新的方法（NIDA研究报告系列，2006年）。我们建议通过使用基于细胞的主要测定法对大型化合物的大量筛选进行高含量筛选，并利用抑制蛋白绿色荧光蛋白报道器直接识别NTR1活化状态的能力，从而鉴定出新型的小分子神经素受体激动剂。该发现计划中的主要优化NTR1激动剂将适用于旨在开发新型医疗疗法以治疗苯丙胺滥用的研究。公共卫生相关性：吸毒是美国的主要社会和经济问题。现在，人们认为，滥用药物最好被归类为大脑疾病，因此应适合医疗疗法。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，激活神经素受体的肽激动剂可以抑制使用苯丙胺的使用。该建议的目的是鉴定小分子神经素受体激动剂。这些化合物将用作研究毒品寻求行为涉及的途径的工具化合物，并可能提供开发新型药物疗法以治疗苯丙胺滥用的基础。