Incorporation of dihydroartemisinin into memantine through a propriate spacer to make hybrid with enhanced effects to protect PC12 cells from corticosterone-caused impairments

Ten memantine(Mema)-dihydroartemisinin(DHA) ligands were designed and synthesized. Three types of isomers including α , β , and a defined γ 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 artemisinin(Arte). The β Mema/DHA ligands are a little bit more cytotoxic than α 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 neuro-protective activities against the insults. However, two ligands, 2 a( β ) and 2 b( 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 confirmed 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 cells and might reverse memantine as an anti-depression NMDA antagonist.