Xanomeline新型衍生物SBG-PK-014促进APPsw的α-剪切

发布时间：2018-05-26 21:01

本文选题：xanomeline + SBG-PK-　；参考：《华东师范大学学报(自然科学版)》2014年01期

【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.
[Abstract]:The activation of muscarinic M1 acetylcholine receptor (ACHR) and the 伪 -shear effect of SBG-PK-014, a novel derivative of xanomeline, on APP gene Swedish mutant APPswwere studied. The M _ 1 agonist screening cell model was used to detect the SBG-PK-014 's ECS _ (50) and the maximum response multiple of Fasta. The effects of the compound and xanomeline on the secretion of sAPP 伪 were analyzed by overexpression of APPsW and M1 receptors in N2a cells of mouse neuroblastoma. The results showed that the EC_(50)(40.2 nmol / L of SBG-PK-014 and xanomeline(28.4 nmol / L) were close to those of xanomeline(28.4 nmol / L, but FASCH was 3.5 times as much as that of xanomeline. SBG-PK-014 promoted 伪 -shear of APPsW by activating M1 receptor. At the concentration of 0.1 渭 mol/L and 1 渭 mol/L, the effect of SBG-PK-014 was significantly better than that of xanomeline at the same dose. It can be seen that SBG-PK-014 can activate M1 receptor more effectively than xanomeline, and can also promote 伪 -shear and neuroprotective sAPP 伪 production of APPsW. SBG-PK-014 may have some potential in regulating A 尾 pathological pathway in Alzheimer's disease, and it deserves further study.
【作者单位】：华东师范大学脑功能基因组学教育部重点实验室;北京大学药学院;复旦大学药学院;
【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)
【分类号】：R749.16

【参考文献】