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Review
. 2024;23(4):476-487.
doi: 10.2174/1871527322666230331121028.

Rationale and Development of Tavapadon, a D1/D5-Selective Partial Dopamine Agonist for the Treatment of Parkinson's Disease

Affiliations
Review

Rationale and Development of Tavapadon, a D1/D5-Selective Partial Dopamine Agonist for the Treatment of Parkinson's Disease

Erwan Bezard et al. CNS Neurol Disord Drug Targets. 2024.

Abstract

Currently, available therapeutics for the treatment of Parkinson's disease (PD) fail to provide sustained and predictable relief from motor symptoms without significant risk of adverse events (AEs). While dopaminergic agents, particularly levodopa, may initially provide strong motor control, this efficacy can vary with disease progression. Patients may suffer from motor fluctuations, including sudden and unpredictable drop-offs in efficacy. Dopamine agonists (DAs) are often prescribed during early-stage PD with the expectation they will delay the development of levodopa-associated complications, but currently available DAs are less effective than levodopa for the treatment of motor symptoms. Furthermore, both levodopa and DAs are associated with a significant risk of AEs, many of which can be linked to strong, repeated stimulation of D2/D3 dopamine receptors. Targeting D1/D5 dopamine receptors has been hypothesized to produce strong motor benefits with a reduced risk of D2/D3-related AEs, but the development of D1-selective agonists has been previously hindered by intolerable cardiovascular AEs and poor pharmacokinetic properties. There is therefore an unmet need in PD treatment for therapeutics that provide sustained and predictable efficacy, with strong relief from motor symptoms and reduced risk of AEs. Partial agonism at D1/D5 has shown promise for providing relief from motor symptoms, potentially without the AEs associated with D2/D3-selective DAs and full D1/D5-selective DAs. Tavapadon is a novel oral partial agonist that is highly selective at D1/D5 receptors and could meet these criteria. This review summarizes currently available evidence of tavapadon's therapeutic potential for the treatment of early through advanced PD.

Keywords: D1 agonist; D1/D5 partial dopamine agonist; Dopamine receptors; Parkinson’s disease; direct pathway; indirect pathway; motor symptoms; tavapadon..

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Conflict of interest statement

EB is a director and a shareholder of Motac Neuroscience, Ltd. RK is a current employee of Novartis and owns stock options in the company. DG is a former employee of Cerevel Therapeutics. SD, ML, and CC are employees of Cerevel Therapeutics and may hold stock and stock options in the company.

Figures

Fig. (1)
Fig. (1)
Maximum improvement in UPDRS motor score following treatment with ABT-431 or levodopa in patients with PD [39]. *P < 0.05; P < 0.005, compared with placebo. PD, Parkinson’s disease; UPDRS, Unified Parkinson’s Disease Rating Scale.
Fig. (2)
Fig. (2)
Comparison of tavapadon and levodopa on motor activity in an MPTP-model of PD in nonhuman primates. Higher doses of tavapadon (0.1 and 0.15 mg/kg) led to an improved duration of efficacy versus levodopa. MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson’s disease. Adapted with permission from Young D, Popiolek M, Trapa P, et al. ACS Chem Neurosci 2020; 11(4): 560-6 [33]. ©Copyright 2020 American Chemical Society.

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