Xanomeline新型衍生物SBG-PK-014促进APPsw的α-剪切

王栋; 周宗丽; 高虹; 雷小平; 董素珍; 胡金锋

Xanomeline新型衍生物SBG-PK-014促进APPsw的α-剪切

1.
华东师范大学脑功能基因组学教育部重点实验室, 上海 200062;
2.
北京大学药学院, 北京 100191;
3.
复旦大学药学院, 上海 201203

详细信息

中图分类号: Q291
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出版历程
- 收稿日期: 2013-04-01
- 修回日期: 2013-07-01
- 刊出日期: 2014-01-25

Novel derivative of xanomeline, SBG-PK-014, increases the α-secretion of APPsw

1.
Key Laboratory of Brain Functional Genomics, Ministry of Education, East China Normal University, Shanghai 200062, China;
2.
School of Pharmaceutical Sciences, Peking University, Beijing 100191, China;
3.
School of Pharmacy, Fudan University, Shanghai 201203, China

摘要

摘要: 研究了xanomeline新型衍生物SBG-PK-014对毒蕈碱型M1乙酰胆碱受体的激活能力以及对APP基因瑞典型突变体(APPsw)的-剪切的作用.利用M1激动剂筛选细胞模型检测了SBG-PK-014的EC50和最大响应倍数(FAmax)，并在小鼠神经母细胞瘤N2a细胞中同时过表达APPsw和M1受体，分析了该化合物和xanomeline对sAPP分泌的影响.结果显示，SBG-PK-014的EC50(40.2 nmol/L)与xanomeline (28.4 nmol/L)接近，但FAmax是xanomeline的3.5倍.SBG-PK-014通过激活M1受体促进APPsw的-剪切，且在0.1 mol/L和1 mol/L的浓度下，其效果显著强于同剂量的xanomeline.可见，SBG-PK-014比xanomeline更能有效地激活M1受体，还能促进APPsw的-剪切和神经保护性sAPP的生成，在调节阿尔茨海默病的A病理途径上可能有一定潜力，值得进一步研究.
- xanomeline /
- SBG-PK-014 /
- M1受体激动剂 /
- 阿尔茨海默病 /
- 衰老
Abstract: The activity of a novel derivative of xanomeline, SBG-PK-014, on muscarinic M1 mAChRs and the -secretion of human APP Swedish mutant (APPsw) was evaluated. The EC50 and maximum folds of activation (FAmax) were measured in a cell-based model. Mouse N2a cells over-expressing both APPsw and M1 mAChR gene were treated with SBG-PK-014 and xanomeline, respectively. Their secreation levels of sAPP were then measured using Western Blotting. The results showed that SBG-PK-014 had a similar EC50 to xanomeline (40.2 nmol/L vs. 28.4 nmol/L), but demonstrated a 3.5-fold FAmax, as compared to xanomeline. SBG-PK-014 promoted the -secretion of APPsw via the activation of M1 receptors. At the same dose of 0.1 mol/L and 1 mol/L, SBG-PK-014 exhibited significantly more potent activity. SBG-PK-014 activated M1 receptors more effectively than xanomeline, increased the -cut of APPsw as well as the secretion of neuroprotective sAPP, showed potential in modifying the A pathology of Alzheimers disease (AD), and is worth further development.
- xanomeline /
- SBG-PK-014 /
- M1 agonist /
- Alzheimer′s disease /
- aging

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