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 fir...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.展开更多
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).
文摘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.