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Selective acetylcholinesterase inhibitors derived from muscle relaxant dantrolene.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2019-12-19 , DOI: 10.1016/j.bmcl.2019.126888 Hiroshi Aoyama 1 , Tomohiro Doura 2
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2019-12-19 , DOI: 10.1016/j.bmcl.2019.126888 Hiroshi Aoyama 1 , Tomohiro Doura 2
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Dantrolene, the only therapeutic agent for malignant hyperthermia, is known to have not only a muscle relaxant effect, but also a neuroprotective effect and Alzheimer's disease improving effect. Recently, it has been reported that dantrolene has a weak inhibitory effect on acetylcholinesterase (AChE), which is a therapeutic drug target for Alzheimer's disease. Thus, we focused on developing of AChE inhibitors with benzylpiperidine/piperazine moieties that are based on the dantrolene skeleton. Several derivatives showed an inhibitory activity. Among them, ortho-nitro derivative 8c showed the most potent inhibitory activity with the IC50 value of 34.2 nM. Furthermore, Lineweaver-Burk plot analysis indicated that 8c is AChE-selective inhibitor, which shows only a weak inhibitory effect on butyrylcholinesterase (BuChE) and a non-competitive inhibition.
中文翻译：
选择性乙酰胆碱酯酶抑制剂衍生自肌肉松弛剂丹特罗。
已知丹特罗林是恶性高热的唯一治疗剂，它不仅具有肌肉松弛作用，而且还具有神经保护作用和改善阿尔茨海默氏病的作用。最近，据报道，丹特罗林对乙酰胆碱酯酶（AChE）具有弱的抑制作用，乙酰胆碱酯酶是阿尔茨海默氏病的治疗药物靶标。因此，我们专注于开发具有基于丹特罗骨架的苄基哌啶/哌嗪部分的AChE抑制剂。几种衍生物表现出抑制活性。其中，邻硝基衍生物8c表现出最强的抑制活性，IC50值为34.2 nM。此外，Lineweaver-Burk图分析表明8c是AChE选择性抑制剂，
更新日期：2019-12-20
中文翻译：
选择性乙酰胆碱酯酶抑制剂衍生自肌肉松弛剂丹特罗。
已知丹特罗林是恶性高热的唯一治疗剂，它不仅具有肌肉松弛作用，而且还具有神经保护作用和改善阿尔茨海默氏病的作用。最近，据报道，丹特罗林对乙酰胆碱酯酶（AChE）具有弱的抑制作用，乙酰胆碱酯酶是阿尔茨海默氏病的治疗药物靶标。因此，我们专注于开发具有基于丹特罗骨架的苄基哌啶/哌嗪部分的AChE抑制剂。几种衍生物表现出抑制活性。其中，邻硝基衍生物8c表现出最强的抑制活性，IC50值为34.2 nM。此外，Lineweaver-Burk图分析表明8c是AChE选择性抑制剂，
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