Bis-(-)-nor-meptazinols as Novel Nanomolar Cholinesterase Inhibitors with High Inhibitory Potency on Amyloid-beta Aggregation.

Bis-(-)-nor-meptazinols as Novel Nanomolar Cholinesterase Inhibitors with High Inhibitory Potency on Amyloid-beta Aggregation. Research Abstract Details 

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Bis-(-)-nor-meptazinols as Novel Nanomolar Cholinesterase Inhibitors with High Inhibitory Potency on Amyloid-beta Aggregation. Abstract Text:

Qiong Xie,Hao Wang,Zheng Xia,Meiyan Lu,Weiwei Zhang,Xinghai Wang,Wei Fu,Yun Tang,Wei Sheng,Wei Li,Wei Zhou,Xu Zhu,Zhuibai Qiu,Hongzhuan Chen,

Bis-(-)-nor-meptazinols (bis-(-)-nor-MEPs) 5 were designed and synthesized by connecting two (-)-nor-MEP monomers with alkylene linkers of different lengths via the secondary amino groups. Their acetylcholinesterase (AChE) inhibitory activities were more greatly influenced by the length of the alkylene chain than butyrylcholinesterase (BChE) inhibition. The most potent nonamethylene-tethered dimer 5h exhibited low-nanomolar IC 50 values for both ChEs, having a 10 000-fold and 1500-fold increase in inhibition of AChE and BChE compared with (-)-MEP. Molecular docking elucidated that 5h simultaneously bound to the catalytic and peripheral sites in AChE via hydrophobic interactions with Trp86 and Trp286. In comparison, it folded in the large aliphatic cavity of BChE because of the absence of peripheral site and the enlargement of the active site. Furthermore, 5h and 5i markedly prevented the AChE-induced Abeta aggregation with IC 50 values of 16.6 and 5.8 microM, similar to that of propidium (IC 50 = 12.8 microM), which suggests promising disease-modifying agents for the treatment of AD patients.

Bis-(-)-nor-meptazinols as Novel Nanomolar Cholinesterase Inhibitors with High Inhibitory Potency on Amyloid-beta Aggregation. Publishing Authors By Initials

Q Xie,H Wang,Z Xia,M Lu,W Zhang,X Wang,W Fu,Y Tang,W Sheng,W Li,W Zhou,X Zhu,Z Qiu,H Chen,

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Bis-(-)-nor-meptazinols as Novel Nanomolar Cholinesterase Inhibitors with High Inhibitory Potency on Amyloid-beta Aggregation. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Journal of medicinal chemistry

VOLUME: 51

Page Numbers: 2027-36

Journal Abbreviation: J. Med. Chem.

ISSN: 0022-2623

DAY: 12

MONTH: 03

YEAR: 2008

Bis-(-)-nor-meptazinols as Novel Nanomolar Cholinesterase Inhibitors with High Inhibitory Potency on Amyloid-beta Aggregation. Information

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LANGUAGE: eng

NlmUniqueID: 9716531

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AFFILIATION: zbqiu@shmu.edu.cn, yaoli@shsmu.edu.cn.

Country: United States

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MEDLINETA: J Med Chem

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