Orally Bioavailable Dopamine D1/D5 Receptor-Biased Agonists to Study the Role of β‑Arrestin in Treatment-Related Dyskinesia in Parkinson’s Disease

Dopamine replacement therapies for Parkinson’s disease often produce dyskinesias with long-term use. Published studies suggest that introducing β-arrestin signaling might be protective for dyskinesia. We advanced known noncatecholamine D1/D5 receptor G protein-biased agonists and found that removal of oxygen in the linker from published compounds limited β-arrestin recruitment, whereas introduction of nitrogen on the central o-phenyl linker favored β-arrestin recruitment and provided orally bioavailable compounds. Cryogenic electron microscopy suggested key receptor–ligand interactions influencing the different bias behaviors. We discovered compound 24, a D1/D5 receptor agonist with β-arrestin recruitment and properties for use in vivo. We compared 24 with tavapadon, which shows weak efficacy for β-arrestin signaling, in a rat model of Parkinson’s disease with L-DOPA-induced dyskinesias. At particular doses, compound 24 produced efficacy comparable to L-DOPA, but with fewer concomitant dyskinesias. This first in vivo study suggests that β-arrestin may have a positive influence on reducing dyskinesias following acute administration.