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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >Bis(9)-(-)-nor-meptazinol as a novel dual-binding AChEI potently ameliorates scopolamine-induced cognitive deficits in mice.
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Bis(9)-(-)-nor-meptazinol as a novel dual-binding AChEI potently ameliorates scopolamine-induced cognitive deficits in mice.

机译：Bis（9）-（-）-nor-meptazinol作为一种新型的双结合AChEI可以有效改善东碱诱导的小鼠认知功能障碍。

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Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder which is characterized by the progressive deterioration of cognition and the emergence of behavioral and psychological symptoms in aging patients. Given that the clinical effectiveness of acetylcholinesterase inhibitors (AChEIs) has still been questioned due to dubious disease-modifying effects, the multi-target directed ligand (MTDL) design has become an emerging strategy for developing new drugs for AD treatment. Bis(9)-(-)-nor-meptazinol (Bis-Mep) was firstly reported by us as a novel MTDL for both potent cholinesterase and amyloid-β aggregation inhibition. In this study, we further explored its AChE inhibition kinetic features and cognitive amelioration. Bis-Mep was found to be a mixed-type inhibitor on electric eel AChE by enzyme kinetic study. Molecular docking revealed that two "water bridges" located at the two wings of Bis-Mep stabilized its interaction with both catalytic and peripheral anionic sites of AChE. Furthermore, subcutaneous administration of Bis-Mep (10, 100 or 1000 ng/kg) significantly reversed the scopolamine-induced memory deficits in a typical bell-shaped dose-response manner. The maximal cognitive amelioration of Bis-Mep was achieved at 100 ng/kg, comparable with the effect of a reference drug Huperzine A at 1 mg/kg and also the relevant AChE inhibition in brain. These findings suggested that Bis-Mep might be a promising dual-binding AChE inhibitor for potential AD therapeutics.
机译：阿尔茨海默氏病（AD）是一种多方面的神经退行性疾病，其特征是老年患者的认知能力逐步下降，并出现行为和心理症状。鉴于乙酰胆碱酯酶抑制剂（AChEIs）的临床有效性由于可疑的疾病改良作用而仍受到质疑，因此多靶标定向配体（MTDL）设计已成为开发用于AD治疗的新药的新兴策略。我们首次报道了Bis（9）-（-）-nor-meptazinol（Bis-Mep）作为一种有效抑制胆碱酯酶和β-淀粉样蛋白聚集的新型MTDL。在这项研究中，我们进一步探讨了其对AChE的抑制动力学特征和认知改善。通过酶动力学研究发现，Bis-Mep是电鳗AChE的混合型抑制剂。分子对接揭示了位于Bis-Mep的两个侧翼的两个“水桥”稳定了它与AChE催化和周围阴离子位点的相互作用。此外，Bis-Mep（10、100或1000 ng / kg）的皮下给药以典型的钟形剂量反应方式显着逆转了东amine碱引起的记忆障碍。 Bis-Mep的最大认知改善达到100 ng / kg，可与参考药物石杉碱A的1 mg / kg的作用以及对大脑中相关AChE的抑制作用相媲美。这些发现表明，Bis-Mep可能是潜在AD治疗的有希望的双重结合AChE抑制剂。

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