Nguyen Anh Minh, Semeano Ana, Quach Vianna, Inoue Asuka, Nichols David E, Yano Hideaki
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Center for Drug Discovery, Northeastern University, Boston, MA, USA.
Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
iScience. 2025 Apr 3;28(5):112345. doi: 10.1016/j.isci.2025.112345. eCollection 2025 May 16.
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.
多巴胺D1受体（D1R）与Gαs和Gαolf偶联，在调节神经和神经精神功能方面至关重要。在大脑中，Gαs主要存在于纹状体，而Gαolf在其他部位表达。我们的实验表明，四环儿茶酚激动剂二氢麦角隐亭、甲基二氢麦角隐亭、多黄嘌呤，以及非儿茶酚化合物PF-8294、PF-6142对Gαs偶联表现出完全激动作用，但对Gαolf偶联仅表现出部分激动作用。相比之下，非儿茶酚激动剂他伐帕朵对Gαs表现为完全激动剂，对Gαolf表现为部分激动剂。这些配体对丘脑皮质和纹状体黑质电生理事件，以及对小鼠运动活性和认知功能的影响与其选择性概况一致。这些发现提示了实现区域特异性药理学的可能性，并为开发治疗相关神经和神经精神疾病的D1R药物开辟了新方向。
