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

Autor:	Isaacson SH; Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, USA., Hauser RA; Parkinson's Disease and Movement Disorders Center, Parkinson Foundation Center of Excellence, University of South Florida, Tampa, FL, USA., Pahwa R; Parkinson's Disease and Movement Disorder Center, University of Kansas Medical Center, Kansas City, KS, USA., Gray D; Vigil Neuroscience, Inc, Watertown, MA, USA., Duvvuri S; Cerevel Therapeutics, Boston, MA, USA.
Jazyk:	angličtina
Zdroj:	Clinical parkinsonism & related disorders [Clin Park Relat Disord] 2023 Jul 07; Vol. 9, pp. 100212. Date of Electronic Publication: 2023 Jul 07 (Print Publication: 2023).
DOI:	10.1016/j.prdoa.2023.100212
Abstrakt:	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. Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sridhar Duvvuri reports financial support was provided by Cerevel Therapeutics Inc. Sridhar Duvvuri reports a relationship with Cerevel Therapeutics Inc that includes: employment. Stuart Isaacson has received honoraria for CME for, was a consultant for, received research grants from, and/or served as a promotional speaker on behalf of AbbVie, Acadia Pharmaceuticals Inc., Acorda Therapeutics, Inc., Adamas Pharmaceuticals, Inc., Addex Therapeutics, AFFiRiS AG, Alexza Pharmaceuticals, Allergan, Amarantus BioScience, Amneal Pharmaceuticals LLC, Aptinyx Inc., Bial, Benevolent, Biogen, Biovie, Britannia Pharmaceuticals Ltd, Cala Health, Cerecor Inc., Cerevel Therapeutics, Eli Lilly, Enterin Inc., GE Healthcare, Global Kinetics Pty Ltd, Impax Laboratories, Ipsen, Jazz Pharmaceuticals, Kyowa Kirin, Lundbeck, Merz Pharmaceuticals, Michael J. Fox Foundation, Mitsubishi Tanabe, Neuralys Inc, Neurocrine Biosciences, Inc., Neuroderm, Novartis, Parkinson Study Group, Pharma Two B Ltd., Praxis, Revance, Roche, Sage, Sanofi, Scion, Scion Neurostim, Stoparkinson, Sunovion Pharmaceuticals Inc., Sun Pharma, Supernus Pharmaceuticals, Inc., Theravance Biopharma, Transposon, and UCB. Robert Hauser has received consulting fees from AbbVie, Acadia, Acorda, Adamas, Alterity, Amneal, Aptinyx, Britannia, Cerevance, Curium Pharma, Enterin, Inhibikase, Jazz, KeiferRx, Kyowa Kirin, Lundbeck A/S, Merck, Merz, Neurocrine Biosciences, Novus, Pharma Two B, Pharmather, Revance Therapeutics, Roche, Sage Therapeutics, Scion NeuroStim, Sio Gene Therapies, Sunovion, Supernus, Tolmar, US WorldMeds, and Vivifi Biotech, and has received speaker fees from AbbVie, Acorda, Adamas, Amneal, Kyowa Kirin, Neurocrine Biosciences, and Sunovion. He holds stock in Axial Biotherapeutics and Inhibikase. His institution, University of South Florida, received research fees from AbbVie, Axovant Sciences, Biogen, Bukwang Pharmaceuticals, Cavion, Centogene, Cerevance, Cerevel Therapeutics, Cynapsus Therapeutics, Enterin, F. Hoffmann-La Roche, Genentech, Global Kinetics Corporation, Impax Specialty Pharma, Intec Pharma, Integrative Research Laboratories Sweden AB, Jazz Pharmaceuticals, MJFF, Neuraly, NeuroDerm, Neurocrine Biosciences, Northwestern University, Pfizer, Pharma Two B, Revance Therapeutics, Sanofi US Services, Sun Pharma Advanced Research Company, Sunovion Pharmaceuticals, and UCB Biopharma SPRL. Rajesh Pahwah serves as a consultant for Abbott, AbbVie, ACADIA, Acorda, Amneal, Artemida, Britannia, CalaHealth, Global Kinetics, Impel, Insightec, Jazz, Neuropharma, Kyowa, Neurocrine, PhotoPharmics, Sage, Scineuro, Sunovion, Supernus and XWPharma. He receives research support from Abbott, AbbVie, Addex, Biogen, Biohaven, Boston Scientific, EIP, Global Kinetics, Impax, Intec, Lilly, Neuroderm, Neuraly, Parkinson’s Foundation, Pharma 2B, Prilenia, Roche, Sage, SIS, Sun Pharma, Sunovion, Theranexus, Theravance, and Voyager. David Gray is a former employee of Cerevel Therapeutics and may hold stock and/or stock options in the company. (© 2023 The Authors.)
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