Reconsideration of Anticholinesterase Therapeutic Strategies against Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is well-known as a severe neurodegeneration disease involving complicated etiologies, and cholinesterase inhibition remain the prevailing mode of clinical intervention in AD management. Although most clinically applied cholinesterase inhibitors (ChEIs) achieve limited clinical outcomes, research on the central cholinergic system is still thriving. Recently, an impressive amount of knowledge regarding novel acetylcholinesterase functions, as well as the close association between the central cholinergic system and other key elements for AD pathogenesis, has accumulated, highlighting that this field still has great potential for future drug development. In contrast to the overwhelmingly disappointing clinical therapeutic effects of various disease-modifying drug candidates, interesting evidence has continued to emerge over the past 20 years from the wealth of preclinical and clinical data on the usage of ChEIs, indicating underestimated clinical benefits due to physician ambivalence, a lack of persistent treatment, and inappropriate medication times or doses. Here we pinpoint several topics fit for future attention, focusing on the updated cholinergic hypothesis, especially the pleiotropic relationships with key pathogenetic signaling pathways and functions in AD, as well as possible novel therapeutic strategies, including novel ChEIs and cholinesterase inhibition-based innovative multifunctional therapeutic candidates. We intend to strengthen the future value of the precise application of cholinergic drugs, especially novel ChEIs, as a cornerstone pharmacological approach to AD treatment, either alone or in combination with other targets, to relieve symptoms and to modify disease progression.

Donecopride, a Swiss army knife with potential against Alzheimer's disease

“…Our consortium pursues such a multitarget approach by using multitarget‐directed ligands, which are specifically designed to reach several targets and, consequently, to display synergistic effects without the risk inherent in drug combinations and drug–drug interactions. We recently chose to target both the 5‐HT 4 receptor, in order to exert a potential neuroprotective effect, and AChE (Lecoutey et al, ; Rochais et al, ), whose inhibition remains relevant when associated with a protective effect of the targeted enzyme (Wang & Zhang, ).…”

A Prospective Repurposing of Dantrolene as a Multitarget Agent for Alzheimer’s Disease

“…In addition to MAO inhibition, drugs able to restore appropriate neurotransmitter (namely acetylcholine, ACh) levels found their rationale against AD in the so-called cholinergic theory addressing the inhibition of acetylcholinesterase (AChE) [20]. Albeit most clinically administered AChE inhibitors (AChEIs) show limited or palliative care, research is fervent and interesting perspectives are emerging [21]. In this context, dual-targeting compounds inhibiting AChE and MAOs may significantly slow down the progression of AD, in addition to mitigating its symptoms [22,23].…”

Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

“…Compound 7 docks in the AChE active site with the carbamate group in proximity of Ser203, as imposed by the constraint, but it is positioned much higher in the AChE binding site in two clusters compared to the donepezil and/or the donecopride (Figure 3) [5,6,7,8,9,10,11,12,13]. Consequently, according to our molecular modeling results, compound 7 loses the characteristic interactions of the donecopride ligands family, i.e.,: i) interaction between NH + of piperidine ring through the water molecule lying between the hydroxy groups of two tyrosines (Tyr341 and Tyr337); ii) interaction via C=O group with the backbone NH of Phe295; and iii) the methoxyphenyl moiety is placed a little high but stacking with Trp286 remains possible.…”

“…A unique example of such a pleiotropic anti-AD prodrug is currently reported in literature. Ladostigil ( 1 ) is a carbamate compound which is able to covalently bind to AChE and to liberate a hydroxy derivative of rasagiline, displaying Monoamine Oxidase (MAO)-B inhibitory activity (Figure 2) [6,7,8,9].…”