AChE Inhibition-based Multi-target-directed Ligands, a Novel Pharmacological Approach for the Symptomatic and Disease-modifying Therapy of Alzheimer's Disease

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.

Fig. (1)

Mechanism of action of the enzyme AChE in cholinergic-deficit hypothesis. Revised from Francis PT et al. (2012). Expert Review of Neurotherapeutics, 12, 1351-1365 and Serge G et al. CMAJ, (2002), 166(5), 616-23.

Fig. (2)

The catalytic and peripheral sites of AChE (a) and the binding model of bis(9)-(-)-nor-MEP to AChE (b) and BuChE (c). Xie, Q., Wang, H. et al. Journal of medicinal chemistry 2008, 51(7), 2027-36.

Fig. (3)

Diagram for multifactorial nature of Alzheimer’s disease. Revised from Herrup K, et al. Nature Neuroscience, 2015, 794-799.

Fig. (4)

Structural formula of PMS777 (a) and PMS1339 (b) and the binding model of PMS1339 to AChE (c)

Fig. (5)

Structural formula of a) bis-tacrine derivatives, b), c) bis-MEP derivatives and d) the binding modes of bis-MEP, bis-MEP derivatives (green, purple and yellow, respectively) at the TcAChE gorge.