Characterization of Gαs and Gαolf activation by catechol and non-catechol dopamine D1 receptor agonists

The dopamine D1 receptor (D1R) couples to Gα_s and Gα_olf and is crucial in regulating neurological and neuropsychiatric functions. In the brain, Gα_olf is predominantly found in the striatum whereas Gα_s is expressed elsewhere. Our <i>in vitro</i> 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_s coupling but only partial agonism for Gα_olf coupling. In contrast, the non-catechol agonist tavapadon acted as a full agonist at Gα_olf and a partial agonist at Gα_s. 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 <i>in vitro</i>. 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.