Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor

Authors: Youwen Zhuang, B. Krumm, Huibing Zhang, X. Edward Zhou, Yue Wang, Xi‐Ping Huang, Yongfeng Liu, Xi Cheng, Yi Jiang, Hualiang Jiang, Cheng Zhang, Wei Yi, Bryan L. Roth, Yan Zhang, H. Eric Xu - Cell Research 2021 cited by 99

Dopamine acts as an essential neurotransmitter whose signaling is conducted through five G protein-coupled receptors (GPCRs), dopamine D1 to D5 receptors (DRD1–DRD5). 1 The D1-like receptors, comprising DRD1 and DRD5, primarily couple to the G s family of G proteins to activate adenylyl cyclase and induce cAMP production. DRD1 is the most abundantly expressed dopamine receptor in the CNS. 1 It is the central receptor mediating excitatory dopamine signaling in multiple dopaminergic pathways. Dysregulation of DRD1 signaling has been directly linked to Parkinson’s disease (PD), schizophrenia, and drug abuse. 1 , 2 Due to its fundamental functions in human diseases, DRD1 has long been the subject of intensive drug development efforts toward the treatment of neuropsychiatric diseases. 3 A majority of DRD1 agonists, including the SKF compounds, targets the orthosteric pocket of DRD1, but none has passed clinical trials for neuropsychiatric symptoms to date. 3