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.
