Petzer Jacobus P, Petzer Anel
Department of Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.
Curr Med Chem. 2015;22(8):975-88. doi: 10.2174/0929867322666141215160015.
The current pharmacological therapies for the treatment of Parkinson's disease are mostly inadequate and recent, improved therapeutic agents are required. Two important molecular targets for the design of anti-parkinsonian therapeutic compounds are the adenosine A2A receptor and the enzyme, monoamine oxidase (MAO) B. Adenosine A2A receptor antagonists are a relatively new class of anti-parkinsonian agents, which act by potentiating dopamine-mediated neurotransmission via dopamine D2 receptors. MAO-B inhibitors are established therapy of Parkinson's disease and inhibit the MAO-B-catalysed metabolism of dopamine in the brain. This conserves reduced dopamine stores and extends the action of dopamine. A2A antagonism and MAO-B inhibition have also been associated with neuroprotective effects, further establishing roles for these classes of compounds in Parkinson's disease. Interestingly, caffeine, a known adenosine receptor antagonist, has been recently considered as a lead compound for the design and discovery of A2A antagonists and MAO-B inhibitors. This review summarizes the recent efforts to discover caffeinederived MAO-B inhibitors. The design of caffeine-derived A2A antagonists has been extensively reviewed previously. The prospect of discovering dual-target-directed compounds that act at both targets is also evaluated. Compounds that block the activation and function of both A2A receptors and MAO-B may have a synergistic effect in the treatment of patients with Parkinson's disease.
目前用于治疗帕金森病的药物疗法大多效果不佳，因此需要新的、更有效的治疗药物。抗帕金森病治疗化合物设计的两个重要分子靶点是腺苷A2A受体和单胺氧化酶（MAO）B。腺苷A2A受体拮抗剂是一类相对较新的抗帕金森病药物，其作用机制是通过多巴胺D2受体增强多巴胺介导的神经传递。MAO-B抑制剂是帕金森病的既定治疗方法，可抑制大脑中MAO-B催化的多巴胺代谢。这可以保存减少的多巴胺储备并延长多巴胺的作用时间。A2A受体拮抗作用和MAO-B抑制作用也与神经保护作用有关，进一步确立了这类化合物在帕金森病中的作用。有趣的是，咖啡因是一种已知的腺苷受体拮抗剂，最近被认为是设计和发现A2A拮抗剂和MAO-B抑制剂的先导化合物。本综述总结了最近发现咖啡因衍生的MAO-B抑制剂的研究成果。咖啡因衍生的A2A拮抗剂的设计此前已被广泛综述。本文还评估了发现同时作用于这两个靶点的双靶点导向化合物的前景。同时阻断A2A受体和MAO-B的激活及功能的化合物在治疗帕金森病患者时可能具有协同作用。
