Incorporation of Dihydroartemisinin into Memantine Through a Propriate Spacer to Make Hybrid with Enhanced Effects to Protect PC12 Cells from Corticosterone-caused Impairments

作     者：ZHANG Lei ZHOU Fan ZHANG Laitao PENG Lizhi GUO Cuiping LUO Cheng CHEN Heru 

作者机构：Institute of Traditional Chinese Medicine and Natural Products College of Pharmacy Jinan University Guangzhou 510632 P. R. China State key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 P. R. China Cruangdong Province Key Laboratory of Pharmacodynamic Constituents ofTCA/I and New Drugs Research Jinan University Guangzhou 510632 P. R. China 

出 版 物：《Chemical Research in Chinese Universities》 (高等学校化学研究（英文版）)

年 卷 期：2017年第33卷第4期

页      面：611-622页

核心收录：

学科分类：0710[理学-生物学] 1007[医学-药学(可授医学、理学学位)] 07[理学] 071006[理学-神经生物学] 10[医学] 

基　　金：Supported by the National Natural Science Foundation of China(No.81172982)  the Natural Science Foundation of Guang- dong Province of China(No.2015A030311012) and the Fundamental Research Funds for the Central Universities of China(No. 11615323) 

主　　题：Artemisinm Memantine Neuroprotection N-Methyl-D-aspartate(NMDA) receptor Depression 

摘      要：Ten memantine（Mema）-dihydroartemisinin（DHA） ligands were designed and synthesized. Three types of isomers including α, β, and a defined y isomer were found in each intermediates（1a--1e）. Type γ isomer was firstly reported here and confirmed as a less stable eclipsed conformation. The bonding of Mema with DHA through different carbon chains generally makes the new entities more cytotoxic than either Mema or artemisinm（Arte）. The β Mema/DHA ligands are a little bit more cytotoxic than a ligands. By applying corticosterone（Cort）-impaired PC12 cells models, it was found that Mema and those ligands with more than 3 carbon chains showed weak or no neuroprotective activities against the insults. However, two ligands, 2a（β） and 2b（β） showed better effects than either Arte or their combination（Mema/Arte in 1：1 molar ratio） at a dose of 5 μmol/L. Furthermore, ligands 2a（β）, 2b（β） and 2c（β） were confn-med as mild N-methyl-D-aspartate（NMDA） antagonists, and their corresponding α isomers are weak NMDA antagonists. All the data indicate that the bonding of Mema/DHA in compacted β conformation mode results in enhanced effects against Cort-induced insults in PC12 ceils and might reverse memantine as an anti-depression NMDA antagonist.