Project Summary Tobacco addiction remains a leading cause of death and disease worldwide. Although many individuals express a desire to quit, available therapeutics have proven to be only moderately efficacious, with cessation success rates <25% after one year. In this proposal, we will explore the role of G protein-coupled receptor 3 (GPR3) in modulating nicotine reinforcement and aversion. GPR3 is a constitutively active orphan receptor that activates Gαs leading to increased levels of cAMP within cells. GPR3 is highly expressed in the medial habenula, suggesting it may be a critical modulator of the habenulo-interpeduncular pathway that regulates nicotine aversion. Thus, GPR3 is a novel therapeutic target for nicotine cessation that should be investigated both pharmacologically and mechanistically. However, in vivo studies of GPR3 are restricted due to the limited availability of small molecule ligands for this receptor. The goal of this project is to develop and test probes of GPR3 for in vivo studies related to nicotine abuse. We created a stable HEK hGPR3 cell line and developed multiple in vitro functional assays to evaluate compound activity. We conducted a preliminary structure activity relationship (SAR) study around a GPR3 agonist scaffold and identified a lead compound. During this project, we will conduct a medicinal chemistry campaign to synthesize analogs of our lead scaffold. In addition, we have developed a GPR3 homology model to aid in our SAR analysis. We will determine the potency, efficacy, and selectivity of potential GPR3 agonist probes as well as an initial ADME/PK profile. We hypothesize that optimized probes of GPR3 will decrease self-administration of nicotine by increasing aversive effects through stimulation of the MHb-IPN pathway. We will test the in vivo efficacy of lead GPR3 probes in altering intravenous nicotine self-administration at various nicotine doses. Upon completion of this grant, we expect to have a potent, selective GPR3 agonist probe validated in both cell-based functional assays, and behavioral models of nicotine abuse. Novel GPR3 agonist probes developed under this application will serve as tools to investigate the signaling mechanisms and in vivo functions of GPR3 within the context of health and disease.

Project Narrative G protein-coupled receptor 3 (GPR3) appears to be important in substance abuse and is a novel biological target for nicotine cessation. The goal of this project is to investigate the role of GPR3 in modulating nicotine reinforcement and aversion through development of small molecule compounds that can regulate GPR3 activity.