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

Abstract

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, 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 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.

Keywords

Artemisinin / Memantine / Neuroprotection / N-Methyl-D-aspartate(NMDA) receptor / Depression

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