Discovery of GPR52 ligand probes for cocaine use disorder - PROJECT SUMMARY Abuse of psychostimulants represents a major public health problem in the United States. Continued misuse of stimulants escalates in vulnerable individuals to a substance use disorder (SUD). SUDs are debilitating conditions evidenced by sustained, clinically significant health consequences and there is a critical unmet need to discover therapeutic strategies to normalize mechanistic drivers of cocaine use disorder (CUD) and treat CUD effectively. Using an informatics approach comparing RNA expression in human brain subregions versus other tissues, we identified GPR52, a novel orphan G protein-coupled receptor (GPCR), that is selectively and highly expressed in dopamine D2 receptor (D2R) pathway medium spiny neurons (MSNs) in the nucleus accumbens (NAc). The dopamine (DA) D2R pathway is highly relevant as recent neurocircuitry studies strongly support the hypothesis that D2R striatal reward pathways underlie the processes involved in the development and maintenance of CUD. We have determined that GPR52 is a Gαs/olf-coupled receptor that activates adenylyl cyclase to stimulate production of the second messenger cyclic adenosine monophosphate (cAMP) which induces a functional crosstalk with D2R cAMP signaling and increases NAc D2R MSN excitability. We propose that GPR52 is a promising novel target for CUD and possibly other SUDs. We have recently established and validated GPR52-based cellular assays and designed a novel series of small molecule GPR52 agonists, identifying the tool compound PW0787 which evoked the profile of a selective GPR52 agonist in vitro and in vivo to suppress stimulant-induced psychomotor behavior in mice. In more recent studies, we have identified the first GPR52 G protein-biased agonist probes (e.g., PW0671), which show reduced β-arrestin engagement with reduced GPR52 desensitization. We hypothesize that selective small molecule G protein biased GPR52 agonists will have superior target efficacy and provide an optimal strategy to normalize NAc MSN signaling pathways strongly linked to CUD processes. Our objective is to create and evaluate GPR52 agonist probes with favorable pharmacodynamic and drug metabolism and pharmacokinetics (DMPK) profiles, and evaluate select molecules in proof-of-concept in vivo models. The proposed studies are significant as our discovery program will provide valuable, chemically unique and optimized GPR52 agonists to be explored as SUD therapeutics and serve as neuroprobes to understand fundamental GPR52 mechanisms at cellular, physiological and behavioral levels. The execution of the Aims of this project will considerably advance scientific understanding of GPR52 activation as a therapeutic target, and place us on a trajectory to drive medication development for CUD and possibly other disorders.
