GPR88 Agonist for Alcoholism Treatment

项目摘要 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的慢性复发性疾病。治疗酒精中毒的药物有 有限的功效、严重的副作用和依从性问题。因此，基于新的药物 目标是必要的。孤儿受体GPR88是一种G蛋白偶联受体，其在哺乳动物中具有稳健表达。 纹状体遍布背侧和腹侧区域。多条证据表明GPR88起着重要作用。 在调节纹状体功能中起重要作用，并与饮酒行为有关。我们 使用GPR88敲除小鼠和选择性GPR88激动剂支持物进行的行为研究的初步结果 GPR88激动作用有益于治疗酒精成瘾和依赖的假设。基于 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。在本申请中，我们建议改进我们早期的领先优势， 通过三个迭代的特定目标，化合物产生用于体内研究的GPR88激动剂。目标1： 将优化使用药物的GPR88激动剂的效力、受体选择性和药物样性质， 化学.在目标2中，我们将使用GPR88功能测定（cAMP和GTP酶活性测定）表征化合物。 结合测定）。然后将使用一组ADMET和药代动力学来表征有效化合物 测定。在目标3中，我们将评估在目标1和2中开发的所选化合物在动物中的功效。 饮酒和强化的模型。总体而言，该项目的完成将提供体内探针， 进一步表征GPR88系统并验证GPR88作为治疗的新靶点 酒精中毒

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.