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 GTPS 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.