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Progress in Chemistry 2013, Vol. 25 Issue (11): 1973-1980 DOI: 10.7536/PC130175 Previous Articles   Next Articles

Special Issue: 酶化学

• Review •

Dual Binding Site Acetylcholinesterase Inhibitors

Zheng Wei1,3, Xie Qiong2, Chen Liangkang1,3, Chen Jianxing1,3*, Qiu Zhuibai2*   

  1. 1. NPFPC Key Laboratory of Contraceptives and Devices Research, Shanghai Institute of Planned Parenthood Research, Shanghai 200032;
    2. School of Pharmacy, Fudan University, Shanghai 201203;
    3. Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, Shanghai 200032, China
  • Received: Revised: Online: Published:
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Alzheimer's disease (AD) is becoming a serious threat to life expectancy for elderly people. A hot area of treatments for AD is to develop dual binding site acetylcholinesterase (AChE) inhibitors that simultaneously interact with both the catalytic and peripheral anionic sites of the enzyme. These compounds may act as disease-modifying agents with multiple functions, not only improving cognition of AD patients by elevating acetylcholine levels, but also interfering with β-amyloid (Aβ) aggregation and delaying Aβ-elicited pathological process. Thus, the novel promising dual binding site AChE inhibitors reported in recent years are the focus of this review. Here, we first introduce the action mechanism of dual binding site AChE inhibitors, and then summarize the main classes of dimeric or hybrid compounds, along with the pharmacological profile of the most active candidates for AD therapy. In addition, combined with our preceding studies on (-)-meptazinol-based bivalents, the rational design strategy and structure-activity relationship of dual binding site AChE inhibitors are discussed. The current challenges and development trends are also proposed.

Contents
1 Introduction
2 The action mechanism of dual binding site AChEIs
3 Dual binding site AChE inhibitors
3.1 Homodimers
3.2 Heterodimers
3.3 Dual binding site AChEIs with additional functions
4 Conclusions and outlook

Key words: Alzheimer's disease, drug candidates, dual binding site, acetylcholinesterase inhibitors, Aβ aggregation

CLC Number: 

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