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.
Fangfang Shen,Dingqiang Lu,Xiuquan Ling,Xinxian Wang,Tongqi Liu,Tianhua Huang,Kefei He
In this work, we focus on measuring solubility and analyzing solution thermodynamics of Memantine hydrochloride in different binary solvent mixtures (ethanol + acetonitrile); (ethanol + water); and (ethanol + ethyl acetate) at the temperature range of 278.15–333.15 K under atmospheric pressure. The solubility data was correlated by the modified Apelblat model, the general cosolvency model and the Jouyban-Acree + van't Hoff model. The result show that modified Apelblat equation is best because of the lowest MD data and ethyl acetate could be used as effective anti-solvent in the crystallization process of Memantine hydrochloride In addition, the thermodynamic properties of the solution process, including the Gibbs free energy , enthalpy, and entropy were calculated by the van't Hoff analysis.
Liu Wei,Chen Xiao,Zhao Jing,Yang Chen,Huang Guanqin,Zhang Zhen,Liu Jianjun
Alzheimer’s disease (AD) has an increasing prevalence, complicated pathogenesis and no effective cure. Emerging evidences show that flavonoid compounds such as xanthohumol (Xn) could play an important role as a dietary supplement or traditional Chinese herbal medicine in the management of diseases such as AD. This study aims to analyze the target molecules of Xn in the prevention and treatment of AD, and its potential mechanism from the perspective of metabolites. APP/PS1 mice 2- and 6-months old were treated with Xn for 3 months, respectively, the younger animals to test for AD-like brain disease prevention and the older animals to address therapeutic effects on the disease. Memantine (Mem) was selected as positive control. Behavioral tests were performed to assess the course of cognitive function. Urine samples were collected and analyzed by high-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) coupled with online Compound Discoverer software. Morris Water Maze (MWM) tests showed that Xn, like Mem, had a therapeutic but not a preventive effect on cognitive impairment. The expression levels of urinary metabolites appeared to show an opposite trend at different stages of Xn treatment, downregulated in the prevention phase while upregulated in the therapy phase. In addition, the metabolic mechanisms of Xn during preventive treatment were also different from that during therapeutic treatment. The signaling pathways metabolites nordiazepam and genistein were specifically regulated by Xn but not by Mem in the disease prevention stage. The signaling pathway metabolite ascorbic acid was specifically regulated by Xn in the therapeutic stage. In conclusion, dietary treatment with Xn altered the urinary metabolite profile at different stages of administration in APP/PS1 mice. The identified potential endogenous metabolic biomarkers and signal pathways open new avenues to investigate the pathogenesis and treatment of AD.
危险品化学品经营许可证（带存储）