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

WANG Dong; ZHOU Zong-li; GAO Hong; LEI Xiao-ping; DONG Su-zhen; HU Jin-feng

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Article Navigation > Journal of East China Normal University (Natural Sciences) > 2014 > (1): 123-132

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 Sciences), 2014, (1): 123-132.

Citation:

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 Sciences), 2014, (1): 123-132.

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

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 Date: 2013-04-01
Rev Recd Date: 2013-07-01
Publish Date: 2014-01-25

Abstract

Abstract

The activity of a novel derivative of xanomeline, SBG-PK-014, on muscarinic M1 mAChRs and the -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 sAPP 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 -secretion of APPsw via the activation of M1 receptors. At the same dose of 0.1 mol/L and 1 mol/L, SBG-PK-014 exhibited significantly more potent activity. SBG-PK-014 activated M1 receptors more effectively than xanomeline, increased the -cut of APPsw as well as the secretion of neuroprotective sAPP, showed potential in modifying the A pathology of Alzheimers disease (AD), and is worth further development.
- xanomeline,
- SBG-PK-014,
- M1 agonist,
- Alzheimer′s disease,
- aging

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References

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