Characterization of Gα_sand Gα_olfactivation by catechol and non-catechol dopamine D1 receptor agonists

Abstract

The dopamine D1 receptor (D1R) couples to Gαsand Gαolfand 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, Gαsis widely expressed in the cortex and Gαolfis 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, R03, R05) D1R agonists for their activity at these G proteins. We discovered that these tetracyclic catechol compounds, R03 and R05 exerted full agonism when D1R coupled to Gαsbut partial agonism when D1R coupled to Gαolf. In contrast, tavapadon acted as a full agonist at Gαolfand a partial agonist at Gαs. The effects of these compounds on the cortical and nigral electrophysiological events agree with their selectivity profiles. This suggested the possibility of achieving region-specific pharmacology and opened new directions for developing D1R drugs to treat relevant neurological and neuropsychiatric disorders.