Characterization of Gαsand Gαolfactivation by catechol and non-catechol dopamine D1 receptor agonists

SUMMARY The dopamine D1 receptor (D1R) couples to Gα s and Gα olf and plays a crucial role in regulating voluntary movement and other cognitive functions, making it a potential therapeutic target for several neurological and neuropsychiatric disorders, such as Parkinson’s disease and schizophrenia. In the central nervous system, Gα s is widely expressed in the cortex and Gα olf is predominantly found in the striatum. We used two different configurations of bioluminescence resonance energy transfer (BRET) assays and a fluorescence-based cyclic AMP (cAMP) production functional assay to test a series of tetracyclic catechol (dihydrexidine, methyl-dihydrexidine, doxanthrine) and non-catechol (tavapadon, PF-8294, PF-6142) D1R agonists for their activity at these G proteins. We discovered that these tetracyclic catechol compounds, PF-8294 and PF-6142 exerted full agonism when D1R coupled to Gα s but partial agonism when D1R coupled to Gα olf . In contrast, tavapadon acted as a full agonist at Gα olf and a partial agonist at Gα s . The effects of these compounds on the cortical and nigral electrophysiological events agree with their selectivity profiles. This suggests the possibility of achieving region-specific pharmacology and opens new directions for developing D1R drugs to treat relevant neurological and neuropsychiatric disorders.