Structure–Functional Selectivity Relationship Studies of Apomorphine Analogs to Develop Beta-arrestin Biased-D1/D2R Ligands

Dopamine receptors (D1-5R), responsible for cognition and locomotion, are involved in several neurological diseases. Parkinson’s Disease (PD) is a neurodegenerative disorder wherein patients suffer from the loss of dopaminergic neurons, resulting in both bradykinesia and tremors. Levodopa (L-DOPA) and apomorphine are both effective treatments of PD; however, they both produce severe dyskinesia with chronic use. In a PD model, a recent discovery shows the G-protein pathway is associated with dyskinesia while the beta-arrestin pathway led to locomotor improvement. As of date, there are no known beta-arrestin biased ligands at D1R. Thus, this work focuses on the derivatization of (R)-apomorphine to develop a D1- or D2R beta-arrestin biased ligand through total synthesis or through late-stage functionalization of the core. These analogs will be tested in vitro through collaboration where we will study the structure-functional-selectivity relationship to better assist us in the design of future beta-arrestin biased analogs. The long-term goal of this research is to contribute to the improvement of PD treatment through selective activation of the beta-arrestin pathway. This work is motivated by the severity of L-DOPA induced dyskinesia and the lack of proper, long-term treatment.