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

Abstract

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 (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.

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

CLC Number:

Q291

WANG Dong, ZHOU Zong-li, GAO Hong, LEI Xiao-ping,DONG Su-zhen, HU Jin-feng. Novel derivative of xanomeline, SBG-PK-014, increases the α-secretion of APPsw[J]. Journal of East China Normal University(Natural Sc, 2014, 2014(1): 123-132.

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