Acetylcholinesterase Inhibitors as Disease-Modifying Therapies for Alzheimer’s Disease

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.