Discovery and development of GPR3 agonists for nicotine cessation

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 Gs 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 discover, validate and develop GPR3 agonists for in vivo studies related to nicotine abuse. This will be accomplished by conducting high- throughput virtual screens of millions of compounds from commercial space followed by confirmatory screens in a functional assay. We will then conduct structure activity relationship campaigns on hit scaffolds to determine the potency, efficacy, and selectivity of potential GPR3 agonists as well as initial ADME/PK profiles. 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. In addition, we will characterize GPR3 expression patterns in a brain region and cell type specific manner. 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 agonists 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.