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

Publication ,  Journal Article
Martini, ML; Ray, C; Yu, X; Liu, J; Pogorelov, VM; Wetsel, WC; Huang, X-P; McCorvy, JD; Caron, MG; Jin, J
Published in: ACS Chem Neurosci
September 18, 2019

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.

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Published In

ACS Chem Neurosci

DOI

EISSN

1948-7193

Publication Date

September 18, 2019

Volume

10

Issue

9

Start / End Page

4160 / 4182

Location

United States

Related Subject Headings

  • Receptors, G-Protein-Coupled
  • Receptors, Dopamine D2
  • Receptors, Dopamine D1
  • Dopamine Agonists
  • Dopamine
  • Cyclic AMP
  • Arrestins
  • Antiparkinson Agents
  • Animals
  • 3404 Medicinal and biomolecular chemistry
 

Citation

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Martini, M. L., Ray, C., Yu, X., Liu, J., Pogorelov, V. M., Wetsel, W. C., … Jin, J. (2019). Designing Functionally Selective Noncatechol Dopamine D1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity. ACS Chem Neurosci, 10(9), 4160–4182. https://doi.org/10.1021/acschemneuro.9b00410
Martini, Michael L., Caroline Ray, Xufen Yu, Jing Liu, Vladimir M. Pogorelov, William C. Wetsel, Xi-Ping Huang, John D. McCorvy, Marc G. Caron, and Jian Jin. “Designing Functionally Selective Noncatechol Dopamine D1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity.ACS Chem Neurosci 10, no. 9 (September 18, 2019): 4160–82. https://doi.org/10.1021/acschemneuro.9b00410.
Martini ML, Ray C, Yu X, Liu J, Pogorelov VM, Wetsel WC, et al. Designing Functionally Selective Noncatechol Dopamine D1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity. ACS Chem Neurosci. 2019 Sep 18;10(9):4160–82.
Martini, Michael L., et al. “Designing Functionally Selective Noncatechol Dopamine D1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity.ACS Chem Neurosci, vol. 10, no. 9, Sept. 2019, pp. 4160–82. Pubmed, doi:10.1021/acschemneuro.9b00410.
Martini ML, Ray C, Yu X, Liu J, Pogorelov VM, Wetsel WC, Huang X-P, McCorvy JD, Caron MG, Jin J. Designing Functionally Selective Noncatechol Dopamine D1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity. ACS Chem Neurosci. 2019 Sep 18;10(9):4160–4182.
Journal cover image

Published In

ACS Chem Neurosci

DOI

EISSN

1948-7193

Publication Date

September 18, 2019

Volume

10

Issue

9

Start / End Page

4160 / 4182

Location

United States

Related Subject Headings

  • Receptors, G-Protein-Coupled
  • Receptors, Dopamine D2
  • Receptors, Dopamine D1
  • Dopamine Agonists
  • Dopamine
  • Cyclic AMP
  • Arrestins
  • Antiparkinson Agents
  • Animals
  • 3404 Medicinal and biomolecular chemistry