The therapeutic arsenal for the treatment of Alzheimer’s disease (AD)
remains confined to a group of four inhibitors of AChE and one NMDA receptor
antagonist, which are used to provide a relief of the very late symptoms of the dementia,
i.e. the cognitive and functional decline. In line with the growing body of evidence of
the pivotal role of the β-amyloid peptide (Aβ) in the pathogenesis of AD, alternative
classes of drugs targeting mainly the formation or the aggregation of Aβ are actively
pursued by the pharmaceutical industry, as they could positively modify the course of
AD, stopping or slowing down disease progression. While mostly amyloid-directed
drug candidates are being scrutinized in the past decades as disease-modifying drugs,
mounting preclinical and clinical evidence is pointing towards a disease-modifying role
also for currently marketed anti-Alzheimer AChE inhibitors (AChEIs), particularly for
donepezil. In this review, the neuroprotective effects exhibited by currently
commercialized AChEIs will be briefly discussed, together with the secondary
mechanisms through which they could exert such effects. This review will focus also on
particular classes of AChEIs, namely dual binding site AChEIs, which are being
purposely designed to target Aβ aggregation and/or other biological targets that
contribute to AD pathogenesis, thus constituting very promising disease-modifying anti-
Alzheimer drug candidates.
Keywords: Acetylcholinesterase inhibitors, AChE periperal site, AChE-Aβ
interaction, AP2238 derivatives, Aβ aggregation, bis-tacrines, cannabinoid-based
Aβ aggregation inhibitors, carbamate-based AChEIs, disease-modifying anti-
Alzheimer drugs, dual site binding, huperzine B dimers, lipocrine, marketed
AChEIs, memoquin, multifunctional drugs, neuroprotection, piperidine-based
AChEIs, polyamine-based AChEIs, pyridinium-based AChEIs, tacrine-based
hybrids.