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障碍。现有的治疗酒精中毒的药物有 疗效有限，副作用严重，并存在合规问题。因此，基于新药的新药 目标是必要的。孤儿受体GPR88是一种G蛋白偶联受体，在 整个背部和腹面区域都有纹状体。多条证据表明，GPR88在 在纹状体功能的调节中起重要作用，并与寻酒行为有关。我们的 利用GPR88基因敲除小鼠和选择性GPR88激动剂支持进行行为学研究的初步结果 GPR88激动剂有益于治疗酒精成瘾和依赖的假说。基于 在我们的探测项目R21 MH103708中进行的研究中，我们开发了第一个有效的、选择性的和 脑穿透性小分子GPR88激动剂。在此应用程序中，我们建议提炼我们的早期销售线索 通过三个迭代的特定目标生产用于体内研究的GPR88激动剂的化合物。在目标1中，我们 将使用药物优化GPR88激动剂的效力、受体选择性和类药物特性 化学反应。在目标2中，我们将使用GPR88功能分析(cAMP和GTPS)来表征化合物 结合分析)。然后将使用一组ADMET和药代动力学对有效化合物进行表征 化验。在目标3中，我们将评估目标1和目标2中开发的选定化合物在动物身上的疗效。 饮酒和强化的典范。总体而言，该项目的完成将提供活体探测器 进一步确定GPR88系统的特征，并从药理学角度验证GPR88作为新的治疗靶点 酗酒。

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.