Drug Design and Discovery in Alzheimer’s Disease

Republished Version of Frontiers in Drug Design and Discovery Volume 6

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Specific Cholinesterase Inhibitors: A Potential Tool to Assist in Management of Alzheimer Disease

Pp. 366-386 (21)

Nigel H. Grieg, Mohammad A. Kamal, Nasimudeen R. Jabir, Shams Tabrez, Faizul H. Nasim, Adel M. Abuzenadah and Gjumrakch Aliev

Abstract

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.

Affiliation:

Metabolomics and Enzymology Unit, Fundamental and Applied Biology, King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia.