Structure Activity Relationships of Novel GPR52 Agonists that Suppress Psychostimulant Behavior

Abstract

GPR52 is a class-A orphan G protein-coupled receptor that is selectively expressed in the striatum, and regulates various brain functions through activation of Gs/adenylyl cyclase/cAMP signaling pathways. GPR52 has been identified as a promising drug target for neurological and psychiatric disorders including schizophrenia, substance use disorders, as well as Huntington's disease. We recently synthesized and pharmacologically evaluated a series of novel GPR52 indoline-carboxamide based agonists (Wang, Felsing et al J. Med. Chem. 2020 Nov 25;63(22):13951-13972). Several potent (EC50: ~100 nM) and efficacious GPR52 agonists were identified, and in vivo proof-of-concept investigations revealed that 3 mg/kg of the lead compound PW0787 (12c) displayed antipsychotic-like activity by significantly inhibiting amphetamine-induced hyperlocomotor behavior in mice. Here, we further report our efforts to optimize our molecules for addiction-focused drug discovery in a systematic structure-activity relationship study of pharmacophore features crucial for GPR52 activation. Notably, in a HEK293 cell-based GPR52 cAMP assay, we determined the two lower aromatic moieties of the agonist lead were amenable to further medicinal chemistry with substituents shown to modulate both agonist potency and efficacy. Whereas compound modifications to the carboxamide and heterocyclic linkers were largely detrimental to agonist potency. Surprisingly, when the nitrogen containing ring of the indoline system was broken into more flexible variants, this further increased agonist potency (EC50: ~40 nM) and efficacy, while retaining target selectivity, plasma exposure and serum concentration. Collectively, our findings have resulted in several agonists with optimized potency and efficacy, with PW0787 being an orally bioavailable, brain-penetrant GPR52 agonist. This work also provides valuable pharmacological tools for investigating the physiological and therapeutic potential of GPR52 activation.