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April 1, 2026Journal of Biological ChemistryOpen Access

Structure-guided Discovery of Non-catechol Dopamine D1 Receptor Ligands with Biased Agonism and Antagonism

Yang Zhou William C. Wetsel Alem W. Kahsai Steven H. Olson Lawrence S Barak

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Key Points

The aim is to develop next-generation non-catechol ligands to address the limitations of L-DOPA in Parkinson's disease.
Conducted virtual screening to identify potential D1R ligands.
Optimized structure-activity relationships to enhance selectivity and efficacy.
Evaluated the pharmacokinetics and biased signaling of the identified ligands.
Identified eight novel D1R ligands, including two G protein-biased agonists and four antagonists.
Developed A82R, a non-catechol D1R antagonist with Ki 733 nM and high D1 family selectivity.
Presented A69, a novel -arrestin-biased partial agonist with Ki 86.9 nM and a half-life of 1 hour.

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Implication

Identifies novel dopaminergic ligands, aiming to improve outcomes in Parkinson's disease.

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Cite This Study

Zhou et al. (2026) studied this question.

synapsesocial.com/papers/69f2f0991e5f7920c6386be2 https://doi.org/10.1016/j.jbc.2026.113076

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Keep reading

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

1Functionally selective dopamine D1 receptor endocytosis and signaling by catechol and non-catechol agonists2024 · 1 citations
2Virtual Compound Screening for Discovery of Dopamine D1 Receptor Biased Allosteric Modulators2025 · 3 citations
3A Ligand-Triggered Receptor Conformation Enables the Design of Selective Agonists for the Dopamine 3 Receptor (D <sub>3</sub> R) Using a Bitopic StrategyOriginal Research · 2026 · 1 citations
4Discovery, Characterization, and Optimization of a Novel Positive Allosteric Modulator-Antagonist of the D3 Dopamine Receptor2024
5Discovery, Characterization, and Optimization of a Novel Positive Allosteric Modulator-Antagonist of the D<sub>3</sub> Dopamine Receptor2025 · 2 citations

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