Université de Bordeaux, CNRS Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
Motac Neuroscience, Manchester, United Kingdom.
CNS Neurol Disord Drug Targets. 2024;23(4):476-487. doi: 10.2174/1871527322666230331121028.
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.
目前，用于治疗帕金森病（PD）的疗法无法提供持久且可预测的运动症状缓解，且存在显著的不良反应（AE）风险。虽然多巴胺能药物，特别是左旋多巴，最初可能提供强大的运动控制，但这种疗效可能会随着疾病的进展而变化。患者可能会出现运动波动，包括疗效突然且不可预测的下降。多巴胺激动剂（DAs）通常在 PD 的早期阶段开具，期望它们能延迟与左旋多巴相关的并发症的发展，但目前可用的 DAs 在治疗运动症状方面不如左旋多巴有效。此外，左旋多巴和 DAs 都与显著的 AE 风险相关，其中许多与强烈、重复刺激 D2/D3 多巴胺受体有关。靶向 D1/D5 多巴胺受体被假设可以产生强大的运动益处，同时降低与 D2/D3 相关的 AE 风险，但 D1 选择性激动剂的开发以前受到无法耐受的心血管 AE 和不良药代动力学特性的阻碍。因此，PD 治疗存在未满足的需求，需要具有持久且可预测的疗效、强大的运动症状缓解和降低 AE 风险的治疗方法。D1/D5 的部分激动作用已显示出缓解运动症状的潜力，可能不会出现与 D2/D3 选择性 DAs 和完全 D1/D5 选择性 DAs 相关的 AE。Tavapadon 是一种新型口服部分激动剂，对 D1/D5 受体具有高度选择性，可能符合这些标准。本综述总结了目前关于 tavapadon 治疗早期至晚期 PD 的治疗潜力的现有证据。
