Structure-guided discovery of non-catechol dopamine D1 receptor ligands with biased agonism and antagonism.
Structure-guided discovery of non-catechol dopamine D1 receptor ligands with biased agonism and antagonism.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Durham, US · Author affiliation
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA.Location evidence
La Jolla, US · Author affiliation
Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA. Electronic address: solson@sbpdiscovery.org.Location evidence
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Original abstract
The catechol L-DOPA, a cornerstone of Parkinson's disease (PD) treatment, has two major drawbacks: poor pharmacokinetics and, more significantly, debilitating dyskinesias from chronic dopamine D1 receptor (D1R) activation. Preclinical rodent studies suggest that D1R antagonism or β-arrestin-biased agonism can alleviate these motor complications, highlighting the need for next-generation non-catechol ligands. Through virtual screening, we identified eight novel chemotypes as D1R ligands, including two G protein-biased agonists, two β-arrestin-biased agonists and four antagonists. Structure-activity relationship (SAR) optimization led to the development of A82R, a non-catechol D1R antagonist (Ki 733 nM) with high D1 family over D2 family selectivity. Additionally, we present A69, a novel non-catechol β-arrestin-biased partial agonist for D1R (Ki 86.9 nM, stronger than representative D1R commercial drugs) with a sustained half-life of 1 h in the mouse brain. We show that the observed selectivity patterns are consistent with structural and information-theoretic limits on dopamine's ability to encode receptor subtype identity. Within these bounds, the non-catechol ligand chemotypes represent promising leads for developing therapies that modulate D1R signaling and reduce L-DOPA-induced dyskinesia in PD.