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

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 G_S-biased partial agonists. Administ

SUBMITTER: Martini ML 

PROVIDER: S-EPMC6785188 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature