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含硫美金刚抗氧化剂轭合物作为潜在前药改善阿尔茨海默病的治疗。

Memantine-sulfur containing antioxidant conjugates as potential prodrugs to improve the treatment of Alzheimer's disease.

机构信息

Dipartimento di Farmacia, Università G. D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.

出版信息

Eur J Pharm Sci. 2013 May 13;49(2):187-98. doi: 10.1016/j.ejps.2013.02.013. Epub 2013 Feb 27.

Abstract

The approved treatments for Alzheimer's disease (AD) exploit mainly a symptomatic approach based on the use of cholinesterase inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists. Natural antioxidant compounds, able to pass through the blood-brain barrier (BBB), have been extensively studied as useful neuroprotective agents. A novel approach towards excitotoxicity protection and oxidative stress associated with excess β amyloid (Aβ) preservation in AD is represented by selective glutamatergic antagonists that possess as well antioxidant capabilities. In the present work, GSH (1) or (R)-α-lipoic acid (LA) (2) have been covalently linked with the NMDA receptor antagonists memantine (MEM). The new conjugates, proposed as potential antialzheimer drugs, should act both as glutamate receptor antagonists and radical scavenging agents. The physico-chemical properties and "in vitro" membrane permeability, the enzymatic and chemical stability, the demonstrated "in vitro" antioxidant activity associated to the capacity to inhibit Aβ(1-42) aggregation makes at least compound 2 a promising candidate for treatment of AD patients.

摘要

阿尔茨海默病 (AD) 的批准治疗方法主要采用基于使用胆碱酯酶抑制剂或 N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂的对症治疗方法。能够穿过血脑屏障 (BBB) 的天然抗氧化化合物已被广泛研究作为有用的神经保护剂。一种新的针对兴奋性毒性保护和与 AD 中过量 β 淀粉样蛋白 (Aβ) 保存相关的氧化应激的方法是使用具有抗氧化能力的选择性谷氨酸能拮抗剂。在本工作中,将 GSH(1)或(R)-α-硫辛酸(LA)(2)与 NMDA 受体拮抗剂美金刚(MEM)共价连接。这些新的缀合物被提议作为潜在的抗阿尔茨海默病药物,应该既能作为谷氨酸受体拮抗剂,又能作为自由基清除剂。理化性质和“体外”膜通透性、酶和化学稳定性、与抑制 Aβ(1-42) 聚集能力相关的“体外”抗氧化活性使至少化合物 2 成为治疗 AD 患者的有前途的候选药物。

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