GPR88 Agonist for Alcoholism Treatment

用于治疗酒精中毒的 GPR88 激动剂

基本信息

批准号：
10226303
负责人：
Chunyang Jin
金额：
$ 51.66万
依托单位：
RESEARCH TRIANGLE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226303
关键词：
Ablation Accounting Affect Agonist Alcohol consumption Alcohol dependence Alcoholism Alcohols Animal Model Area Basal Ganglia Behavior Bioavailable Biological Assay Biological Availability Brain Cell Line Cessation of life Chinese Hamster Ovary Cell Chronic Corpus striatum structure Cyclic AMP Development Disease Disulfiram Dopamine Dorsal Dose Drug Kinetics Ethanol Metabolism Evaluation G-Protein-Coupled Receptors GTP Binding GTP-Binding Protein alpha Subunits, Gs Gene Expression Genes Genetic Goals Heavy Drinking Hypersensitivity In Vitro Knockout Mice Lead Locomotion Membrane Metabolic Modification Motivation Mus Naltrexone Names Neuraxis Neurons Neurotransmitters Opioid Oral Orphan Palate Parkinson Disease Patients Penetration Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Play Process Property Public Health Rattus Regulation Relapse Research Rewards Rodent Role Sampling Schizophrenia Self Administration Series Societies Specificity Structure Structure-Activity Relationship Synaptic plasticity System Testing Therapeutic Therapeutic Agents United States Food and Drug Administration Water consumption Wild Type Mouse Work acamprosate alcohol behavior alcohol preferring rats alcohol reinforcement alcohol seeking behavior alcohol testing alcohol use disorder alcoholism therapy base behavioral phenotyping behavioral study conditioned place preference cost dopamine system drinking effective therapy efficacy evaluation improved in vivo medication compliance mouse model novel novel therapeutics preclinical study problem drinker programs receptor receptor function scaffold side effect small molecule

项目摘要

Project Summary The goal of this project is to develop GPR88 agonists to treat alcohol use disorders. Alcoholism is a heterogeneous, chronic relapsing disorder. Available medications to treat alcoholism have limited efficacy, serious side effects, and compliance issues. Therefore, new medications based on novel targets are needed. The orphan receptor GPR88 is a G-protein-coupled receptor with robust expression in the striatum throughout the dorsal and ventral areas. Multiple lines of evidence suggest that GPR88 plays an important role in the regulation of striatal functions and is implicated in alcohol-seeking behaviors. Our preliminary results in behavioral studies using GPR88 knockout mice and a selective GPR88 agonist support the hypothesis that GPR88 agonism is beneficial to treat alcohol addiction and dependence. Based on the research conducted in our probe project R21 MH103708, we have developed the first potent, selective, and brain-penetrant small molecule GPR88 agonists. In this application, we propose to refine our early lead compounds to produce GPR88 agonists for in vivo studies through three iterative specific aims. In Aim 1, we will optimize potency, receptor selectivity, and drug-like properties of GPR88 agonists using medicinal chemistry. In Aim 2, we will characterize compounds using GPR88 functional assays (cAMP and GTPS binding assays). Potent compounds will then be characterized using a battery of ADMET and pharmacokinetic assays. In Aim 3, we will evaluate the efficacy of select compounds, developed in Aims 1 and 2, in animal models of alcohol drinking and reinforcement. Overall, completion of this project will provide in vivo probes to further characterize the GPR88 system and pharmacologically validate GPR88 as a novel target for treatment of alcoholism.

项目概要该项目的目标是开发 GPR88 激动剂来治疗酒精使用障碍。酒精中毒是一种异质性、慢性复发性疾病，目前有治疗酒精中毒的药物。疗效有限、副作用严重以及依从性问题，因此，基于新颖的新药物。孤儿受体 GPR88 是一种 G 蛋白偶联受体，在多个证据表明 GPR88 在整个背侧和腹侧区域的纹状体中发挥着重要作用。在纹状体功能的调节中发挥重要作用，并与我们的饮酒行为有关。使用 GPR88 敲除小鼠和选择性 GPR88 激动剂支持进行行为研究的初步结果 GPR88 激动剂有益于治疗酒精成瘾和依赖的假设。在我们的探针项目 R21 MH103708 中进行的研究中，我们开发了第一个有效的、选择性的、脑渗透性小分子 GPR88 激动剂在此应用中，我们建议完善我们的早期先导药物。在目标 1 中，我们通过三个迭代的具体目标来生产用于体内研究的 GPR88 激动剂。将使用药物优化 GPR88 激动剂的效力、受体选择性和药物样特性在目标 2 中，我们将使用 GPR88 功能测定（cAMP 和 GTP-S）表征化合物。然后将使用一系列 ADMET 和药代动力学来表征有效的化合物。在目标 3 中，我们将评估目标 1 和 2 中开发的选定化合物在动物中的功效。总体而言，该项目的完成将为饮酒和强化模型提供体内探针。进一步表征 GPR88 系统并从药理学角度验证 GPR88 作为新的治疗靶点酗酒。