Xanomeline新型衍生物SBG-PK-014促进APPsw的α-剪切  

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

作　　者：王栋[1] 周宗丽 高虹[1] 雷小平[2] 董素珍[1] 胡金锋[1,3] 

机构地区：[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

出　　处：《华东师范大学学报（自然科学版）》2014年第1期123-132,共10页Journal of East China Normal University(Natural Science)

基　　金：国家自然科学基金项目(31000574;90713040);国家重点基础研究发展计划(973计划)(2013CB530700)

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α-剪切的作用.利用M1激动剂筛选细胞模型检测了SBG-PK-014的EC_(50)和最大响应倍数(FA_(max)),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sAPPα分泌的影响.结果显示,SBG-PK-014的EC_(50)(40.2 nmol/L)与xanomeline(28.4 nmol/L)接近,但FA_(max)是xanomeline的3.5倍.SBG-PK-014通过激活M1受体促进APPsW的α-剪切,且在0.1μmol/L和1μmol/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α-剪切和神经保护性sAPPα的生成,在调节阿尔茨海默病的Aβ病理途径上可能有一定潜力,值得进一步研究.The activity of a novel derivative of xanomeline, SBG-PK-014, on muscarinic M1 mAChRs and the s-secretion of human APP Swedish mutant （APPsw） was evaluated. The EC50s and maximum folds of activation （FAmax） were measured in α cell-based model. Mouse N2a cells over expressing both APPsw and M1 mAChR gene were treated with SBG-PK-014 andxanomeline, respectively. Their secreation levels of sAPPa were then measured using Western Blotting. The results showed that SBG-PK 014 had a similar ECso to xanomeline （40.2 nmol/L VS. 014 O. 1 28.4 nmol/L）, but demonstrated a 3.5-fold FA as promoted the a secretion of APP /lmol/L and 1 μmol/L, SBG-PK to xanomeline. SBG PK sw via the activation of M1 receptors. At the same dose of 014 exhibited significantly more potent activity. SBG-PK- 014 activated M1 receptors more effectively than xanomeline, increased the α cut of APPsw as well as the secretion of neuroprotective sAPPy, showed potential in modifying the Aβ pathology of Alzheimer＇s disease （AD）, and is worth further development.

关 键 词：XANOMELINE SBG—PK-014 M1受体激动剂 阿尔茨海默病 衰老 

分 类 号：Q291[生物学—细胞生物学]