Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 50005; Hradec Kralove, Czech Republic.
Curr Alzheimer Res. 2013 Oct;10(8):893-906. doi: 10.2174/1567205011310080011.
Alzheimer´s disease (AD) is a progressive neurodegenerative dementia which currently represents one of the biggest threats for the human kind. The cure is still unknown and various hypotheses (cholinergic, amyloidal, oxidative, vascular etc.) are investigated in order to understand the pathophysiology of the disease and on this basis find an effective treatment. Tacrine, the first approved drug for the AD disease treatment, has been reported to be a multitargeted drug, however it was withdrawn from the market particularly due to its hepatotoxicity. Its derivative 7-methoxytacrine (7- MEOTA) probably due to the different metabolization does not exert this side effect. The aim of our study was to compare these two cholinesterase inhibitors from various, mainly cholinergic, points of view relevant for a potential AD drug. We found that 7-MEOTA does not fall behind its more well-known parent compound - tacrine. Furthermore, we found, that 7-MEOTA exerts better properties in most of the tests related to a possible AD treatment. Only the pharmacokinetics and a higher acetylcholinesterase and butyrylcholinesterase inhibitory potency would slightly give advantages to tacrine over 7-MEOTA, but concerning its lower toxicity, better antioxidant properties, interaction with muscarinic and nicotinic receptors and "safer" metabolization provide strong evidence for reconsider 7-MEOTA and its derivatives as candidate molecules for the treatment of AD.
阿尔茨海默病（AD）是一种进行性神经退行性痴呆症，目前是人类面临的最大威胁之一。目前还没有治愈方法，人们正在研究各种假说（胆碱能、淀粉样、氧化、血管等），以了解疾病的病理生理学，并在此基础上找到有效的治疗方法。他克林是第一种被批准用于治疗 AD 的药物，据报道它是一种多靶点药物，但由于其肝毒性已从市场上撤出。其衍生物 7-甲氧基他克林（7-MEOTA）可能由于代谢方式不同，不会产生这种副作用。我们的研究目的是从各种主要与潜在 AD 药物相关的胆碱能角度比较这两种胆碱酯酶抑制剂。我们发现 7-MEOTA 并不逊于更为知名的母体化合物他克林。此外，我们发现 7-MEOTA 在大多数与可能的 AD 治疗相关的测试中表现出更好的特性。只有药代动力学和更高的乙酰胆碱酯酶和丁酰胆碱酯酶抑制活性略优于他克林，但考虑到其较低的毒性、更好的抗氧化特性、与毒蕈碱和烟碱受体的相互作用以及“更安全”的代谢，为重新考虑 7-MEOTA 及其衍生物作为 AD 治疗候选药物提供了有力证据。
