β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer's Disease Therapy
β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer's Disease Therapy
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DOI：
10.1021/acs.jmedchem.0c01887
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发表时间：
2021-02-02
影响因子：
7.3
通讯作者：
Haudecoeur, Romain
中科院分区：
文献类型：
--
作者：
Beato, Aurelien;Gori, Anthonin;Haudecoeur, Romain
天然的β-咔啉生物碱显示出与神经递质的相似性，可以有利地利用其来设计用于阿尔茨海默病（AD）治疗的生物活性和生物可利用的药物。目前正在深入研究几种AD靶点，分为不同的假设：主要是胆碱能、淀粉样蛋白β（A β）和Tau假设。迄今为止，只有对症治疗，涉及乙酰胆碱酯酶和NMDA抑制剂。基于多靶点构效关系研究，β-咔啉支架被确定为促进活性和与广泛AD相关靶点的分子相互作用的有力工具。这些知识无疑可以用于设计多靶点定向配体，这是一种在具有复杂病因学的多因素病理学（如AD）背景下优选的高度相关策略。在这篇综述中，我们首先单独讨论β-咔啉的AD靶标，然后我们专注于致力于精心设计新的高效支架的多靶标策略。
The natural beta-carboline alkaloids display similarities with neurotransmitters that can be favorably exploited to design bioactive and bioavailable drugs for Alzheimer's disease (AD) therapy. Several AD targets are currently and intensively being investigated, divided in different hypotheses: mainly the cholinergic, the amyloid beta (A beta), and the Tau hypotheses. To date, only symptomatic treatments are available involving acetylcholinesterase and NMDA inhibitors. On the basis of plethoric single-target structure-activity relationship studies, the beta-carboline scaffold was identified as a powerful tool for fostering activity and molecular interactions with a wide range of AD-related targets. This knowledge can undoubtedly be used to design multitarget-directed ligands, a highly relevant strategy preferred in the context of multifactorial pathology with intricate etiology such as AD. In this review, we first individually discuss the AD targets of the beta-carbolines, and then we focus on the multitarget strategies dedicated to the deliberate design of new efficient scaffolds.