Characterization of Gα and Gα activation by catechol and non-catechol dopamine D1 receptor agonists.

The dopamine D1 receptor (D1R) couples to Gα and Gα and is crucial in regulating neurological and neuropsychiatric functions. In the brain, Gα is predominantly found in the striatum whereas Gα is expressed elsewhere. Our assays revealed that the tetracyclic catechol agonists dihydrexidine, methyl-dihydrexidine, doxanthrine, and the non-catechol compounds PF-8294, PF-6142 exerted full agonism for Gα coupling but only partial agonism for Gα coupling. In contrast, the non-catechol agonist tavapadon acted as a full agonist at Gα and a partial agonist at Gα. The effects of these ligands on the thalamocortical and striatonigral electrophysiological events, as well as on the locomotor activity and cognitive function of mice agreed with their selectivity profiles . These findings suggest the possibility of achieving region-specific pharmacology and open new directions for developing D1R drugs to treat relevant neurological and neuropsychiatric disorders.