Xanomeline新型衍生物SBG"PK-014促进APPsw的cr剪切简

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EC₅₀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EC₅₀(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0.1 μmol/L和1 μmol/L的浓度下，其效果显著强于同剂量的xanomeline.可见，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.

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

The activity of a novel derivative of xanomeline, SBG-PK-014, on muscarinic M1 mAChRs and the α-secretion of human APP Swedish mutant (APPsw) was evaluated. The EC₅₀ and maximum folds of activation (FA_max) 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 sAPPα 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 FA_max, as compared to xanomeline. SBG-PK-014 promoted the α-secretion of APPsw via the activation of M1 receptors. At the same dose of 0.1 μmol/L and 1 μmol/L, SBG-PK-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 sAPPα, showed potential in modifying the Aβ pathology of Alzheimer’s disease (AD), and is worth further development.