Virtual Compound Screening for Discovery of Dopamine D1 Receptor Biased Allosteric Modulators

The dopamine D1 receptor (D1R) is a therapeutic target for a variety of central nervous system disorders including Parkinson's disease (PD). Challenges thus arise in the development of safer D1R therapies in limiting off-target drug activity. This issue is particularly relevant to PD therapy, where L-DOPA has been the "gold standard" drug for decades despite a problematic side-effect profile. Recent studies of G-protein and β-arrestin functionally selective signaling offer new strategies for developing superior D1R orthosteric and allosteric compounds with fewer side effects. We designed a desktop-computer drug-screening platform to examine large virtual chemical libraries for allosteric compounds binding D1R intracellular loop 2 (ICL2) determinants. Two structurally distinct hits were strong enhancers of dopamine-induced β-arrestin recruitment and inhibitors of dopamine-induced G-protein activation. The lead candidate DUSBI-A3 was highly selective for D1R over closely related dopamine receptors when assessed by β-arrestin activation, providing proof-of-concept for pursuing D1R selective, biased compounds in the treatment of PD.