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

Dopamine receptors are important G protein-coupled receptors (GPCRs) with therapeutic opportunities for treating Parkinson's Disease (PD) motor and cognitive deficits. Biased D-1 dopamine ligands that differentially activate G protein over beta-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 D-1-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. 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 D-1 receptor signaling biology and biased agonism in models of neurologic disease.