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

Abstract

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