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具有乙酰胆碱酯酶（AChE）抑制和 5-羟色胺能 4 型受体（5-HT4R）激动活性的新型多靶点定向配体（MTDLs）作为潜在的阿尔茨海默病治疗药物：去甲多塞平的设计。

Novel multitarget-directed ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HT4R) agonist activities as potential agents against Alzheimer's disease: the design of donecopride.

机构信息

†UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032 Caen, France.

‡CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France.

出版信息

J Med Chem. 2015 Apr 9;58(7):3172-87. doi: 10.1021/acs.jmedchem.5b00115. Epub 2015 Mar 31.

DOI:10.1021/acs.jmedchem.5b00115
PMID:25793650
Abstract

In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer's disease.

摘要

在这项工作中，我们描述了一系列新型的多靶点导向配体（MTDL）的合成和体外评估，这些配体具有纳摩尔级的双重结合位点（DBS）乙酰胆碱酯酶抑制作用和部分 5-HT4R 激动剂活性，其中多奈哌齐被选为进一步在小鼠体内进行评估。后者显示出认知促进和抗健忘作用，并增强了 sAPPα 的释放，这为治疗阿尔茨海默病提供了一种潜在的对症和疾病修饰治疗益处。

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