Discovery of an Allosteric Agonist for Schizophrenia Risk Gene GPR52 with Antipsychotic Activity

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<b>Abstract ID 27887</b> <b>Poster Board 537</b> GPR52, recently identified by GWAS as a schizophrenia risk gene, is a brain orphan G protein-coupled receptor. GPR52 is primarily expressed in D2 medium spiny neurons in the human striatum, particularly the nucleus accumbens. This unique expression profile of GPR52 suggests that the receptor may functionally regulate cAMP signaling to oppose the activity of dopamine D2 receptors. This distinguishes GPR52 as an attractive target for numerous psychiatric disorders, including schizophrenia and substance use disorders. Here we report our efforts to elucidate GPR52 neuronal signaling and to discover selective agonists for this receptor. In molecular signaling studies, expression of low levels of human GPR52 in wildtype HEK293 cells elevated basal cAMP levels over 100-fold, with further elevation of cAMP in response to the agonist FTBMT. This cAMP response was eliminated by stable knockout of G_s/olf proteins using CRISPR/Cas9 genome editing. Iterative medicinal chemistry design and pharmacological evaluation of novel small molecules led to the optimized GPR52 agonist PW0787. PW0787 increased GPR52 cAMP signaling with good potency (EC50: 135nM) and efficacy (300% over basal), while exhibiting excellent target selectivity, brain penetrance, and serum concentration. Molecular docking of PW0787 into the GPR52 crystal structure suggested compound binding with extracellular loop 2 (ECL2) and an allosteric mode of action. In a whole cell patch clamp study using mouse brain slices, PW0787 increased the frequency and number of evoked action potentials in D2, but not D1, medium spiny neurons of the nucleus accumbens. In this study, PW0787 also rescued neuronal excitability to basal levels after treatment with the dopamine D2 receptor agonist quinpirole. Dose-dependent testing of PW0787 revealed 3 and 10 mg/kg treatments in mice significantly reduced amphetamine-induced hyperlocomotion, indicating antipsychotic-like activity. Together, these findings indicate that GPR52, via G_s/olf cAMP signaling, is a highly constitutively active, excitatory receptor selectively expressed in D2 medium spiny neurons. Our drug discovery effort has resulted in novel GPR52 activators with PW0787 being a potent, selective, orally bioavailable, brain-penetrant agonist that excites D2 medium spiny neurons and shows antipsychotic-like activity. Functional alterations of striatal cAMP signaling by GPR52 may help explain why the receptor is a schizophrenia risk gene. These findings further support that GPR52 is a druggable target with therapeutic potential for treating psychiatric disorders. <b>Acknowledgements:</b> The UTMB Center for Addiction Research, NIDA 1U18DA052543-01 (JAA), and 2022 PhRMA Foundation Pre-Doctoral Fellowship in Drug Discovery (REM).