Title:Advances in Dopamine D1 Receptor Ligands for Neurotherapeutics
Volume: 19
Issue: 16
Author(s): Daniel E. Felsing, Manish K. Jain and John A. Allen*
Affiliation:
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, 77555-0615,United States
Keywords:
Positive allosteric modulator, Cognitive disorders, Biased signaling, Non-catechol, Dopamine, D1 receptor, G protein-
coupled receptor, Structure-activity relationships.
Abstract: The dopamine D1 receptor (D1R) is essential for neurotransmission in various brain pathways
where it modulates key functions including voluntary movement, memory, attention and reward.
Not surprisingly, the D1R has been validated as a promising drug target for over 40 years and selective
activation of this receptor may provide novel neurotherapeutics for neurodegenerative and neuropsychiatric
disorders. Several pharmacokinetic challenges with previously identified small molecule D1R
agonists have been recently overcome with the discovery and advancement of new ligands, including
drug-like non-catechol D1R agonists and positive allosteric modulators. From this, several novel molecules
and mechanisms have recently entered clinical studies. Here we review the major classes of D1R
selective ligands including antagonists, orthosteric agonists, non-catechol biased agonists and positive
allosteric modulators, highlighting their structure-activity relationships and medicinal chemistry. Recent
chemistry breakthroughs and innovative approaches to selectively target and activate the D1R also hold
promise for creating pharmacotherapy for several neurological diseases.