中文摘要：

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-PK014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sAPPa分泌的影响．结果显示，SBG—PK-014的EC-50（40．2nmol／L）与xanomeline（28．4nmol／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a一剪切，且在0．1／μmol／L和1／μmol／L的浓度下，其效果显著强于同剂量的xanomeline．可见，SBGPK014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sAPPa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．

英文摘要：

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.