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一种新型四氢吖啶衍生物具有强大的乙酰胆碱酯酶抑制特性和体外研究证实的对 Aβ42 纤维的解离能力。

A Novel Tetrahydroacridine Derivative with Potent Acetylcholinesterase Inhibitory Properties and Dissociative Capability against Aβ42 Fibrils Confirmed by In Vitro Studies.

机构信息

Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.

Department of Respiration Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.

出版信息

Int J Mol Sci. 2024 Sep 19;25(18):10072. doi: 10.3390/ijms251810072.

Abstract

Alzheimer's disease (AD) is one of the most common causes of dementia, accounting for more than 60% of all cases. It is a neurodegenerative disease in which symptoms such as a decline in memory, thinking, learning, and organizing skills develop gradually over many years and eventually become more severe. To date, there is no effective treatment for the cause of Alzheimer's disease, and the existing pharmacological options primarily help manage symptoms. Treatment is mainly based on acetylcholinesterase (AChE) inhibitors such as donepezil, rivastigmine, and galantamine, which exhibit numerous adverse cardiovascular and gastrointestinal effects due to excessive stimulation of peripheral cholinergic activity involving muscarinic receptors. Therefore, in addition to the obvious drugs that act on the cause of the disease, new drugs based on AChE inhibition that show the fewest side effects are needed. One potential drug could be a new compound under study, tetrahydroacridine derivative (CHDA), which showed significant potential to inhibit the AChE enzyme in previous in vitro studies. The present study shows that while having very potent AChE inhibitory properties, CHDA is a compound with low toxicity to nerve cell culture and living organisms. In addition, it exhibits dissociative activity against amyloid β fibrils, which is extremely important for applications in Alzheimer's disease therapy.

摘要

阿尔茨海默病(AD)是痴呆症最常见的原因之一,占所有病例的 60%以上。它是一种神经退行性疾病,其症状如记忆力、思维、学习和组织技能逐渐下降,多年后最终变得更加严重。迄今为止,尚无有效的治疗方法来治疗阿尔茨海默病的病因,现有的药物选择主要用于治疗症状。治疗主要基于乙酰胆碱酯酶(AChE)抑制剂,如多奈哌齐、加兰他敏和石杉碱甲,由于过度刺激涉及毒蕈碱受体的外周胆碱能活性,这些药物会引起许多不良的心血管和胃肠道作用。因此,除了针对疾病原因的明显药物外,还需要基于 AChE 抑制作用的新型药物,这些药物的副作用最小。一种潜在的药物可能是一种正在研究的新化合物,即四氢吖啶衍生物(CHDA),它在之前的体外研究中显示出显著抑制 AChE 酶的潜力。本研究表明,CHDA 虽然具有很强的 AChE 抑制特性,但对神经细胞培养和活体的毒性很低。此外,它对淀粉样β纤维表现出分离活性,这对于阿尔茨海默病治疗的应用非常重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750c/11444201/73cf5d61f554/ijms-25-10072-g001.jpg

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