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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，作为一种新型双重结合ACHEI，其特殊地改善了小鼠中的COLOPOLAMINE诱导的认知缺陷。

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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：阿尔茨海默病（AD）是一种多方面的神经变性障碍，其特征在于认知的逐步恶化以及老年患者的行为和心理症状的出现。鉴于乙酰胆碱酯酶抑制剂（ACHEIS）的临床效果仍然受到可疑的疾病改性效应，多目标定向配体（MTDL）设计已成为开发新药的新出现策略。 BIS（9） - （ - ） - 由我们首先将NOR-Meptazinol（BIS-MEP）作为一种用于效率的胆碱酯酶和淀粉样蛋白-β聚集抑制的新型MTDL。在这项研究中，我们进一步探讨了其疼痛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是一种混合型抑制作用电鳗疼痛的抑制剂。分子对接显示，位于双MEP的两个翅膀的两个“水桥”稳定其与ache的催化和周边阴离子位点相互作用。此外，皮下施用BIS-MEP（10,100或1000ng / kg）以典型的钟形剂量 - 响应方式显着逆转到COLOPOLAMINE诱导的记忆缺陷。 BIS-MEP的最大认知改善以100ng / kg实现，与参考药物Huperzine a的效果相当，并且在脑中的相关疼痛抑制也是如此。这些发现表明，BIS-MEP可能是潜在的AD治疗剂的有希望的双重结合ACHE抑制剂。

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