Journal of East China Normal University(Natural Sc ›› 2014, Vol. 2014 ›› Issue (1): 123-132.

• Article • Previous Articles     Next Articles

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

WANG Dong1, ZHOU Zong-li1, GAO Hong1, LEI Xiao-ping2,DONG Su-zhen1, HU Jin-feng1,3   

  1. 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
  • Received:2013-04-01 Revised:2013-07-01 Online:2014-01-25 Published:2015-09-25

Abstract: 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 (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 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 FAmax, 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.

Key words: xanomeline, SBG-PK-014, M1 agonist, Alzheimer’s disease, aging

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