Open AccessStructure–Functional–Selectivity Relationship Studies of Novel Apomorphine Analogs to Develop D1R/D2R Biased Ligands
Author(s) -
Hyejin Park,
Aarti N. Urs,
James J. Zimmerman,
Chuan Liu,
Wang Qiu,
Nikhil M. Urs
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00575
Subject(s) - dopamine , functional selectivity , apomorphine , dopamine receptor d2 , neuroscience , dopamine receptor , parkinson's disease , motor symptoms , receptor , chemistry , pharmacology , dopaminergic , medicine , biology , disease , g protein coupled receptor , biochemistry
Loss of dopamine neurons is central to the manifestation of Parkinson's disease motor symptoms. The dopamine precursor L-DOPA, the most commonly used therapeutic agent for Parkinson's disease, can restore normal movement yet cause side-effects such as dyskinesias upon prolonged administration. Dopamine D1 and D2 receptors activate G-protein- and arrestin-dependent signaling pathways that regulate various dopamine-dependent functions including locomotion. Studies have shown that shifting the balance of dopamine receptor signaling toward the arrestin pathway can be beneficial for inducing normal movement, while reducing dyskinesias. However, simultaneous activation of both D1 and D2Rs is required for robust locomotor activity. Thus, it is desirable to develop ligands targeting both D1 and D2Rs and their functional selectivity. Here, we report structure-functional-selectivity relationship (SFSR) studies of novel apomorphine analogs to identify structural motifs responsible for biased activity at both D1 and D2Rs.