Structure-guided discovery of non-catechol dopamine D1 receptor ligands with biased agonism and antagonism.
Overview
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA
- Departments of Psychiatry and Behavioral Sciences and Neurobiology, Duke University Medical Center, Durham, North Carolina, USA
- Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
- Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
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.
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Data
Datasets cited
- github.com/
barak-group , at github.com; found in “Data availability”
Data availability
All data generated or analyzed during this study are included in this published article, its supplementary information files and the GitHub repository (https://
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Versions
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Version 1, 30 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 7 keywords, 10 MeSH terms, 1 funder, 43 references.
Cite
This paper
Zhou, Y., Wetsel, W. C., Kahsai, A. W., Olson, S. H., & Barak, L. S. (2026). Structure-guided discovery of non-catechol dopamine D1 receptor ligands with biased agonism and antagonism. The Journal of biological chemistry, 302(6), 113076. https://
BibTeX
@article{zhou2026structu
author = {Zhou, Yang and Wetsel, William C. and Kahsai, Alem W. and Olson, Steven H. and Barak, Lawrence S.},
title = {{Structure-guided discovery of non-catechol dopamine D1 receptor ligands with biased agonism and antagonism}},
journal = {The Journal of biological chemistry},
year = {2026},
month = apr,
volume = {302},
number = {6},
pages = {113076},
publisher = {American Society for Biochemistry and Molecular Biology},
issn = {0021-9258},
doi = {10.1016/
url = {https://
pmid = {42055336},
pmcid = {PMC13218150}
}
RIS
TY - JOUR
AU - Zhou, Yang
AU - Wetsel, William C.
AU - Kahsai, Alem W.
AU - Olson, Steven H.
AU - Barak, Lawrence S.
TI - Structure-guided discovery of non-catechol dopamine D1 receptor ligands with biased agonism and antagonism
T2 - The Journal of biological chemistry
J2 - J Biol Chem
PY - 2026
DA - 2026/
VL - 302
IS - 6
SP - 113076
SN - 0021-9258
PB - American Society for Biochemistry and Molecular Biology
DO - 10.1016/
UR - https://
LA - en
ER -
CSL-JSON
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"language": "en",
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