Title:AChE Inhibition-based Multi-target-directed Ligands, a Novel Pharmacological Approach for the Symptomatic and Disease-modifying Therapy of Alzheimer’s Disease
VOLUME: 14 ISSUE: 4
Author(s):Yu Wang, Hao Wang and Hong-zhuan Chen
Affiliation:Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China., Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
Keywords:Acetylcholinesterase inhibitor, alzheimer’s disease, multi-target-directed ligand.
Abstract:Alzheimer's disease (AD) is the most common form of dementia in elder
people, characterised by a progressive decline in memory as a result of an
impairment of cholinergic neurotransmission. To date acetylcholinesterase inhibitors
(AChEIs) have become the most prescribed drugs for the symptomatic treatment of
mild to moderate AD. However, the traditional “one molecule-one target” paradigm
is not sufficient and appropriate to yield the desired therapeutic efficacy since
multiple factors, such as amyloid-β (Aβ) deposits, neuroinflammation, oxidative stress, and decreased levels of
acetylcholine (ACh) have been thought to play significant roles in the AD pathogenesis. New generation of multi-target
drugs is earnestly demanded not only for ameliorating symptoms but also for modifying the disease. Herein, we delineated
the catalytic and non-catalytic functions of AChE, and summarized the works of our group and others in research and
development of novel AChEI-based multi-target-directed ligands (MTDLs), such as dual binding site AChEIs and multitarget
AChEIs inhibiting Aβ aggregation, regulating Aβ procession, antagonizing platelet-activating factor (PAF) receptor,
scavenging oxygen radical, chelating metal ions, inhibiting monoamine oxidase B (MAO-B), blocking N-methyl-D-aspartic
acid (NMDA) receptor and others.
