The catechol L-DOPA, a cornerstone of Parkinson's disease (PD) treatment, has two major drawbacks: poor pharmacokinetics and, more significantly, debilitating dyskinesias from chronic dopamine D1 receptor (D1R) activation.Preclinical rodent studies suggest that D1R antagonism or -arrestin-biased agonism can alleviate these motor complications, highlighting the need for next-generation non-catechol ligands.Through virtual screening, we identified eight novel chemotypes as D1R ligands, including two G protein-biased agonists, two -arrestin-biased agonists and four antagonists.Structure-activity relationship (SAR) optimization led to the development of A82R, a non-catechol D1R antagonist (Ki 733 nM) with high D1 family over D2 family selectivity.Additionally, we present A69, a novel non-catechol -arrestin-biased partial agonist for D1R (Ki 86.9 nM, stronger than representative D1R commercial drugs) with sustained half-life of 1 hour in mouse brain.We show that the observed selectivity patterns are consistent with structural and information-theoretic limits on dopamine's ability to encode receptor subtype J o u r n a l P r e -p r o o f identity.Within these bounds the non-catechol ligand chemotypes represent promising leads for developing therapies that modulate D1R signaling and reduce L-DOPA-induced dyskinesia in PD.
Zhou et al. (Wed,) studied this question.