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当代阿耳茨海默病研究

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

美金刚和6-氯罗他林的组合作为新型抗阿尔茨海默氏病的多目标化合物

卷 16, 期 9, 2019

页: [821 - 833] 页: 13

弟呕挨: 10.2174/1567205016666190228122218

价格: $65

摘要

背景：阿尔茨海默氏病（AD）是老年人中最常见的痴呆形式。它被表征为具有普遍遗传成分的多因素疾病。由于病因不明，目前基于乙酰胆碱酯酶（AChE）抑制剂和N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂的治疗仅是暂时有效的。由于该疾病的多因素性质，看来治愈性治疗必将是复杂的。在这种情况下，已经建立了所谓的“多目标”方法。 目的：这项研究的目的是开发一种多目标定向配体（MTDL），通过抑制AChE结合对胆碱能系统的支持，同时减轻由NMDAR受体介导的谷氨酸兴奋性毒性引起的负担。 方法：我们采用有机化学的常用方法制备了6-氯他克林和美金刚的混合物。然后，我们调查了其对AChE和NMDRS的体外阻断能力，以及在NMDA诱导的减退模型中的体内神经保护功效。我们还研究了该化合物的细胞毒性潜力，并预测了穿越血脑屏障的能力。 结果：由6-氯他克林和美金刚结合形成的新型分子被证明是一种有前途的多能杂种，能够阻断AChE和NMDAR的作用。提出的杂种超过母体化合物6-Cl-THA的AChE抑制活性两倍。根据结果，我们的新杂种以与美金刚相同的方式阻断NMDAR，有效抑制AChE，并预计将通过被动扩散穿过血脑屏障。最后，体内结果表明了MTDL设计策略，该结果表明新型6-Cl-THA-美金刚杂种比母体化合物美金刚在定量上表现出更好的神经保护作用。 结论：我们得出的结论是，将具有共同作用机制的两种药效基团组合成一个分子，为治疗与NMDAR介导的认知能力下降和/或兴奋性毒性相关的CNS疾病提供了巨大的潜力。

关键词: 6-氯罗他命，美金刚，乙酰胆碱酯酶，NMDA受体，阿尔茨海默氏病，离子通道，膜片钳技术。

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