engleski

Evaluation of 4-aminoquinolines as potential anticholinesterase agents in the treatment of Alzheimer`s disease

Over the past years, although great efforts have been devoted to the development of drugs to treat Alzheimer’s disease (AD), five of the six currently approved AD drugs act by temporally improving the cognitive abilities of patients by increasing the amount of the neurotransmitter acetylcholine or by blocking NMDA receptors in the brain. The problem in the development of AD drugs that act to slow or stop the progression of the disease lies in the fact that the aetiology of the disease is highly complex with clinical hallmarks such as a decline in acetylcholine levels, amyloid-β (Aβ ) peptide deposits, oxidative stress, dyshomeostasis of bio-metals, tau protein hyper phosphorylation and accumulation , all concomitant with the fact that expression and level of appearance of AD hallmarks are highly individual. Recently, the new approach was suggested, that future research directed to slowing down or stopping the progression of AD and preserving brain function should move from single targeted drugs to "multi-target directed ligands”. In line with that, one of the most promising direction s combines the inhibition of ACh hydrolysis and additional AD features that target the promotion or progression of the disease, like oxidative stress and/or reduction of amyloid plaques aggregation. Design of new cholinesterase inhibitors, particularly acetylcholinesterase inhibitors, preferably includes "dual-binding site" inhibitors able to simultaneously interact with the catalytic and peripheral anionic sites of the enzyme. Such ligands have the potential to restore the cholinergic deficit by blocking acetylcholinesterase catalytic activity and at the same time interfering with Aβ deposition and aggregation by interaction with acetylcholinesterase’s peripheral anionic site . Such desired characteristics could be met by 4- aminoquinolines. T heir simple structure, high inhibitory potential toward cholinesterases and potential to cross the blood - brain barrier make 4-aminoquinoline derivatives a promising candidate for the design of novel AD drugs.

4-aminoquinolines ; Alzheimer`s disease ; cholinesterases

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