Dopamine agonists in Parkinson's disease: Impact of D1-like or D2-like dopamine receptor subtype selectivity and avenues for future treatment

Stuart H Isaacson; Robert A Hauser; Rajesh Pahwa; David Gray; Sridhar Duvvuri

doi:10.1016/j.prdoa.2023.100212

Dopamine agonists in Parkinson's disease: Impact of D1-like or D2-like dopamine receptor subtype selectivity and avenues for future treatment

Clin Park Relat Disord. 2023 Jul 7:9:100212. doi: 10.1016/j.prdoa.2023.100212. eCollection 2023.

Authors

Stuart H Isaacson¹, Robert A Hauser², Rajesh Pahwa³, David Gray⁴, Sridhar Duvvuri⁵

Affiliations

¹ Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, USA.
² Parkinson's Disease and Movement Disorders Center, Parkinson Foundation Center of Excellence, University of South Florida, Tampa, FL, USA.
³ Parkinson's Disease and Movement Disorder Center, University of Kansas Medical Center, Kansas City, KS, USA.
⁴ Vigil Neuroscience, Inc, Watertown, MA, USA.
⁵ Cerevel Therapeutics, Boston, MA, USA.

Abstract

Dopamine agonists (DAs) have demonstrated efficacy for the treatment of Parkinson's disease (PD) but are limited by adverse effects (AEs). DAs can vary considerably in their receptor subtype selectivity and affinity, chemical composition, receptor occupancy, and intrinsic activity on the receptor. Most currently approved DAs for PD treatment primarily target D2/D3 (D2-like) dopamine receptors. However, selective activation of D1/D5 (D1-like) dopamine receptors may enable robust activation of motor function while avoiding AEs related to D2/D3 receptor agonism. Full D1/D5 receptor-selective agonists have been explored in small, early-phase clinical studies, and although their efficacy for motor symptoms was robust, challenges with pharmacokinetics, bioavailability, cardiovascular AEs, and dyskinesia rates similar to levodopa prevented clinical advancement. Generally, repeated dopaminergic stimulation with full DAs is associated with frontostriatal dysfunction and sensitization that may induce plastic changes in the motor system, and neuroadaptations that produce long-term motor and nonmotor complications, respectively. Recent preclinical and clinical studies suggest that a D1/D5 receptor-selective partial agonist may hold promise for providing sustained, predictable, and robust motor control, while reducing risk for motor complications (e.g., levodopa-induced dyskinesia) and nonmotor AEs (e.g., impulse control disorders and excessive daytime sleepiness). Clinical trials are ongoing to evaluate this hypothesis. The potential emerging availability of novel dopamine receptor agonists with selective dopamine receptor pharmacology suggests that the older terminology "dopamine agonist" may need revision to distinguish older-generation D2/D3-selective agonists from D1/D5-selective agonists with distinct efficacy and tolerability characteristics.

Keywords: D1 receptors; D2 receptors; Direct pathway; Dopamine agonists; Dopamine receptor selectivity; Parkinson’s disease; Parkinson’s disease treatment; Partial agonism.

Publication types

Review