School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China.
Mini Rev Med Chem. 2021;21(15):2039-2064. doi: 10.2174/1389557521666210212151127.
Alzheimer's disease (AD) is a progressive neurodegenerative disease with concealed onset, which is characterized by the damage of the cholinergic system, deposition, and accumulation of β- amyloid protein (Aβ) and neurofibrillary tangles. Because the cholinergic system plays a key role in the process of brain memory, it has become one of the important targets in anti-AD research. In view of the complicated pathological characteristics of AD, the multi-target directed ligands (MTDLs) that can act on multiple targets are considered to be an effective treatment strategy at present. Tacrine, as the first acetylcholinesterase (AChE) inhibitor, has been discontinued because of its hepatotoxicity, but its core structure is simple and easy to modify. By using tacrine to target the active catalytic site (CAS), the tacrine-based MTDLs can act on both CAS and peripheral anion site (PAS) of AChE to serve as a dual-site AChE inhibitor. Additionally, the tacrine-based MTDLs can also be designed on the basis of other theories of AD, for example, introducing functional moieties to modulate the formation of β-amyloid (Aβ), oxidation resistance, or metal chelation. In this paper, the research progress of tacrine-based MTDLs is summarized.
阿尔茨海默病（AD）是一种隐匿起病的进行性神经退行性疾病，其特征为胆碱能系统损伤、β-淀粉样蛋白（Aβ）沉积和积聚以及神经纤维缠结。由于胆碱能系统在大脑记忆过程中起着关键作用，因此它已成为抗 AD 研究的重要靶点之一。鉴于 AD 的复杂病理特征，目前认为能够作用于多个靶点的多靶标导向配体（MTDLs）是一种有效的治疗策略。他克林作为第一个乙酰胆碱酯酶（AChE）抑制剂，由于其肝毒性已被停用，但它的核心结构简单，易于修饰。通过以他克林为靶标作用于活性催化位点（CAS），基于他克林的 MTDLs 可以同时作用于 AChE 的 CAS 和外周阴离子位点（PAS），作为双位点 AChE 抑制剂。此外，还可以基于 AD 的其他理论来设计基于他克林的 MTDLs，例如，引入功能基团来调节β-淀粉样蛋白（Aβ）的形成、抗氧化或金属螯合。本文总结了基于他克林的 MTDLs 的研究进展。
