CHOLINESTERASE INHIBITION AS STARTING POINT FOR A MORE EFFECTIVE TREATMENT OF ALZHEIMER’S DISEASE

The extensive loss of cholinergic neurotransmission and the abnormal aggregation and deposition of amyloid-beta-peptide (A-beta) are retained as key events in Alzheimer’s disease (AD) and represent appealing targets for drug discovery strategies. Although the inhibition of acetylcholinesterase (AChE) has been the major available therapeutic strategy for AD patients in the past two decades, the rationale at the basis of the use of AChE inhibitors has evolved. Indeed, though the understanding of the relationship between AChE and other pathological features of AD is incomplete, experimental evidence has shown that AChE can influence A-beta aggregation while inhibition of butyrylcholinesterase might be beneficial in moderate/advanced forms of AD. Together with enlarged knowledge of AD molecular mechanisms, these findings have opened new avenues in AD drug discovery. In particular, multi-potent compounds, namely AChE dual binding site inhibitors endowed with other properties such as A-beta aggregation inhibition and metal chelating and/or anti-oxidant properties, may provide therapeutic benefits. In vitro characterization of the mechanism of action of new multi-potent compounds was pursued by purposely designed methodologies such as colorimetric, fluorometric methods and circular dichroism. This approach has allowed the selection of promising new chemical entities, which could be further developed for an effective treatment of AD.