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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Martini, ML; Ray, C; Yu, X; Liu, J; Pogorelov, VM; Wetsel, WC; Huang, X-P; McCorvy, JD; Caron, MG; Jin, J

Published Date

  • September 18, 2019

Published In

Volume / Issue

  • 10 / 9

Start / End Page

  • 4160 - 4182

PubMed ID

  • 31387346

Pubmed Central ID

  • 31387346

Electronic International Standard Serial Number (EISSN)

  • 1948-7193

Digital Object Identifier (DOI)

  • 10.1021/acschemneuro.9b00410

Language

  • eng

Conference Location

  • United States