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 <i>o</i>-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 <b>24</b>, a D1/D5 receptor agonist with β-arrestin recruitment and properties for use <i>in vivo</i>. We compared <b>24</b> 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 <b>24</b> produced efficacy comparable to L-DOPA, but with fewer concomitant dyskinesias. This first <i>in vivo</i> study suggests that β-arrestin may have a positive influence on reducing dyskinesias following acute administration.