Pharmacophore-based design and discovery of (−)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis

Abstract

Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer’s disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (−)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate 43 was highly potent (IC₅₀ 31.6 nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, 43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism. 43 also showed amyloid-β (Aβ) lowering effects (51.9% decrease of Aβ₄₂) superior to phenserine (31% decrease of total Aβ) in SH-SY5Y-APP₆₉₅ cells at 50 µM. The dual actions of 43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.

Keywords:

• Pharmacophore
• carbamates
• (−)-meptazinol
• acetylcholinesterase
• amyloidogenesis

Acknowledgements

We thank Professor Shengdi Chen, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, for providing the SH-SY5Y-APP₆₉₅ cells.

Disclosure statement

The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This work was supported by the National Basic Research Program of China (973 Program, 2010CB529806); National Major Scientific and Technological Special Project for ?Significant New Drugs Development? of Ministry of Science and Technology of China (2009ZX09103-077 and 2009ZX09301-011); National Natural Science Foundation of China (30772553, 30801393, 30801435, 30973509, 21202098, 81373395 and 81573415); Ph.D. Programs Foundation of Ministry of Education of China (200802461095); Science and Technology Commission of Shanghai Municipality (10431902700, 14431905600); and “Chen Guang” Project of Shanghai Municipal Education Commission and Shanghai Education Development Foundation (10CG03).