Accompanying the gradual rise in the average age of the population of most
industrialized countries is a regrettable escalation in individuals afflicted with
progressive neurodegenerative disorders, epitomized by Alzheimer's disease (AD). The
development of effective new treatment strategies for AD has therefore become one of
the most critical challenges in current neuroscience. Cholinesterase inhibitors (ChEIs)
remain the primary therapeutic strategy for AD, and act by amplifying residual
cholinergic activity, a neurotransmitter system central in cognitive processing that is
reported to be depleted in the AD brain. With the recent failure of current drug classes
focused towards the molecular events known to underpin AD, including the generation
of amyloid-β peptide (Aβ) containing plaques and neurofibrillary tangles (hyperphosphorylated
tau). The development of new generation of cholinergic drugs has been
accomplished to take advantage of the known modulatory action of the cholinergic
system on Aβ, tau production as well as the maintenance synapses, which are known to
be lost in AD. Following upon the development of acetylcholinesterase inhibitors
(AChE-Is), phenserine, that additionally possessed amyloid precursor protein (APP)
synthesis inhibitory actions to lower the generation of Aβ. Selective butyrylcholinesterase
inhibitors (BuChE-Is), cymserine analogues, have been developed on the same chemical
backbone during further anti-AD research advancement. The above mentioned
inhibitors retain actions on APP as well as Aβ and amplify central cholinergic actions
without the classical dose-limiting adverse effect profile; therefore, these current
BuChE-Is are now moving into AD clinical trials.
Keywords: Acetylcholinesterase, acetylcholinesterase inhibitors, Alzheimer
disease, amyloid-β peptide, amyloid precursor protein, butyrylcholinesterase
inhibitors, cholinesterases, clinical trials, cymserine, dementia, glial cells, inhibitors,
kinetic analysis, muscle disorders, neurodegenerative disorders, neurotransmitters,
synaptic cleft, tau protein.
