2. Academic Validation
  3. Designing Functionally Selective Noncatechol Dopamine D1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity

Designing Functionally Selective Noncatechol Dopamine D1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity

  • ACS Chem Neurosci. 2019 Sep 18;10(9):4160-4182. doi: 10.1021/acschemneuro.9b00410.
Michael L Martini 1 2,  Caroline Ray 3,  Xufen Yu 1,  Jing Liu 1,  Vladimir M Pogorelov 3 4 5,  William C Wetsel 3 4 5,  Xi-Ping Huang 6,  John D McCorvy 7,  Marc G Caron 3 5,  Jian Jin 1
Affiliations

Affiliations

  • 1 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
  • 2 Medical Scientist Training Program , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
  • 3 Department of Cell Biology , Duke University Medical Center , Durham , North Carolina 27710 , United States.
  • 4 Departments of Psychiatry and Behavioral Sciences , Duke University Medical Center , Durham , North Carolina 27710 , United States.
  • 5 Department of Medicine and Neurobiology , Duke University Medical Center , Durham , North Carolina 27710 , United States.
  • 6 Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program, School of Medicine , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.
  • 7 Department of Cell Biology, Neurobiology and Anatomy , Medical College of Wisconsin , Milwaukee , Wisconsin 53226 , United States.
PMID: 31387346 DOI: 10.1021/acschemneuro.9b00410
Abstract

Dopamine receptors are important G protein-coupled receptors (GPCRs) with therapeutic opportunities for treating Parkinson's Disease (PD) motor and cognitive deficits. Biased D1 dopamine ligands that differentially activate G protein over β-arrestin recruitment pathways are valuable chemical tools for dissecting positive versus negative effects in drugs for PD. Here, we reveal an iterative approach toward modification of a D1-selective noncatechol scaffold critical for G protein-biased agonism. This approach provided enhanced understanding of the structural components critical for activity and signaling bias and led to the discovery of several novel compounds with useful pharmacological properties, including three highly GS-biased partial agonists. Administration of a potent, balanced, and brain-penetrant lead compound from this series results in robust antiparkinsonian effects in a rodent model of PD. This study suggests that the noncatechol ligands developed through this approach are valuable tools for probing D1 receptor signaling biology and biased agonism in models of neurologic disease.

Keywords

D dopamine receptor; Parkinson’s disease; biased agonism; dyskinesia; noncatechol agonists; structure−functional selectivity relationship; β-arrestins.

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