GPR88 Agonist for Alcoholism Treatment

用于治疗酒精中毒的 GPR88 激动剂

• 批准号: 10459403
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459403
• 关键词: Ablation; Accounting; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Area; Basal Ganglia; Behavior; 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

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.

项目摘要 该项目的目的是开发GPR88激动剂来治疗酒精使用障碍。 酒精中毒是一种异质，慢性复发障碍。可用的药物治疗酒精中毒 有限的有效性，严重的副作用和合规性问题。因此，基于小说的新药物 需要目标。孤儿受体GPR88是一种G蛋白偶联受体，在 纹状体遍布整个背侧和腹侧区域。多种证据表明GPR88扮演 在调节纹状体功能中的重要作用，并在寻求酒精的行为中实施。我们的 使用GPR88敲除小鼠和选择性GPR88激动剂支持的行为研究的初步结果 GPR88激动剂对治疗酒精成瘾和依赖性有益的假设。基于 在我们的探针项目R21 MH103708中进行的研究，我们开发了第一个有效，选择性和 脑培训剂小分子GPR88激动剂。在此应用程序中，我们建议完善我们的早期潜在客户 通过三个迭代特定目的产生体内研究的GPR88激动剂的化合物。在AIM 1中，我们 将使用医学上的GPR88激动剂优化GPR88激动剂的效力，受体选择性和类似药物的特性 化学。在AIM 2中，我们将使用GPR88功能分析（CAMP和GTPS）来表征化合物 绑定测定）。然后，有效的化合物将使用一系列ADMET和药代动力学来表征 测定。在AIM 3中，我们将评估Aims 1和Aim 2中开发的精选化合物的效率 饮酒和加固的模型。总体而言，该项目的完成将为体内问题提供 进一步将GPR88系统和药物验证为GPR88作为治疗的新目标 酒精中毒。

项目成果

Improvement of the Metabolic Stability of GPR88 Agonist RTI-13951-33: Design, Synthesis, and Biological Evaluation.

GPR88 激动剂 RTI-13951-33 代谢稳定性的改善：设计、合成和生物学评估。

• DOI: 10.1021/acs.jmedchem.2c01983
• 发表时间: 2023-02-23
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Rahman, Md Toufiqur;Decker, Ann M.;Ben Hamida, Sami;Perrey, David A.;Lakmal, Hetti Handi Chaminda;Maitra, Rangan;Darcq, Emmanuel;Kieffer, Brigitte L.;Jin, Chunyang
• 通讯作者: Jin, Chunyang