Inadequacies of the current pharmacotherapies to treat Parkinson’s disease (PD) have prompted efforts to identify novel drug targets. The adenosine A_2A receptor is one such target. Antagonists of this receptor (A_2A antagonists) are considered promising agents for the symptomatic treatment of PD. Evidence suggests that A_2A antagonists may also have neuroprotective properties that may prevent the development of the dyskinesia that often complicates levodopa treatment. Because the therapeutic benefits of A_2A antagonists are additive to that of dopamine replacement therapy, it may be possible to reduce the dose of the dopaminergic drugs and therefore the occurrence of side effects. Inhibitors of monoamine oxidase (MAO)-B also are considered useful tools for the treatment of PD. When used in combination with levodopa, inhibitors of MAO-B may enhance the elevation of dopamine levels after levodopa treatment, particularly when used in early stages of the disease when dopamine production may not be so severely compromised. Furthermore, MAO-B inhibitors may also possess neuroprotective properties in part by reducing the damaging effect of dopamine turnover in the brain. These effects of MAO-B inhibitors are especially relevant when considering that the brain shows an age-related increase in MAO-B activity. Based on these observations, dual-target-directed drugs, compounds that inhibit MAO-B and antagonize A_2A receptors, may have value in the management of PD. This review summarizes recent efforts to develop such dual-acting drugs using caffeine as the lead compound.

中文翻译：

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阻断帕金森病的单胺氧化酶 B 和腺苷 A(2A) 受体的双靶向药物。

当前治疗帕金森病 (PD) 的药物疗法的不足促使人们努力确定新的药物靶点。腺苷A _2A受体就是这样的一个靶点。该受体的拮抗剂（A _2A拮抗剂）被认为是有希望用于 PD 对症治疗的药物。有证据表明，A _2A拮抗剂也可能具有神经保护特性，可以防止经常使左旋多巴治疗复杂化的运动障碍的发展。因为 A _2A的治疗益处拮抗剂是多巴胺替代疗法的添加剂，有可能减少多巴胺能药物的剂量，从而减少副作用的发生。单胺氧化酶 (MAO)-B 抑制剂也被认为是治疗 PD 的有用工具。当与左旋多巴联合使用时，MAO-B 抑制剂可能会增加左旋多巴治疗后多巴胺水平的升高，尤其是在疾病的早期阶段使用时，多巴胺的产生可能不会受到如此严重的影响。此外，MAO-B 抑制剂也可能具有神经保护特性，部分原因是通过减少大脑中多巴胺周转的破坏作用。MAO-B 抑制剂的这些作用在考虑到大脑显示出与年龄相关的 MAO-B 活性增加时尤其重要。基于这些观察，_2A受体，可能在 PD 的管理中具有价值。本综述总结了最近使用咖啡因作为先导化合物开发此类双作用药物的努力。