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

Anh Minh Nguyen; Ana Semeano; Vianna Quach; Asuka Inoue; David E Nichols; Hideaki Yano

doi:10.1016/j.isci.2025.112345

Characterization of Gα_s and Gα_olf activation by catechol and non-catechol dopamine D1 receptor agonists

iScience. 2025 Apr 3;28(5):112345. doi: 10.1016/j.isci.2025.112345. eCollection 2025 May 16.

Authors

Anh Minh Nguyen¹, Ana Semeano¹, Vianna Quach¹, Asuka Inoue², David E Nichols³, Hideaki Yano¹

Affiliations

¹ Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Center for Drug Discovery, Northeastern University, Boston, MA, USA.
² Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
³ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.

Abstract

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 in vitro 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 in vitro. 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.

Keywords: Molecular biology; Neuroscience.