Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis

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dc.contributor.author Kamal, MA
dc.contributor.author Qu, X
dc.contributor.author Yu, Q-S
dc.contributor.author Tweedie, D
dc.contributor.author Holloway, HW
dc.contributor.author Li, Y
dc.contributor.author Tan, Y
dc.contributor.author Greig, NH
dc.date.accessioned 2010-05-28T09:51:32Z
dc.date.issued 2008-06
dc.identifier.citation Journal of Neural Transmission, 2008, 115 (6), pp. 889 - 898
dc.identifier.issn 0300-9564
dc.identifier.other C1 en_US
dc.identifier.uri http://hdl.handle.net/10453/9736
dc.description.abstract Synaptic loss, particularly related to the forebrain cholinergic system, is considered to be an early event that leads to Alzheimer's disease (AD) and has led to the development of acetylcholinesterase inhibitors (AChE-Is) as the mainstay of treatment for several degenerative disorders that culminate in dementia. The primary dose-limiting toxicities of all clinically available AChE-Is are, similar to useful actions on cognition, cholinergically mediated and they ultimately limit the value of this drug class in achieving anything but symptomatic improvements. In addition, AChE levels in brain areas associated with AD decline with disease progression, which likely ultimately limits the therapeutic utility of this drug class. New research indicates that selective inhibition of butyrylcholinesterase (BuChE), a closely related enzyme that is markedly elevated in AD brain, increases acetylcholine (ACh) and augments cognition in rodents free of the characteristic undesirable actions of AChE-Is. BuChE inhibition hence represents an innovative treatment approach for AD, and agents are currently being synthesized to optimally achieve this. The novel compound, tetrahydrofurobenzofuran cymserine (THFBFC), is derived from our effort to produce a potent and BuChE-selective inhibitor as a candidate to test the hypothesis that BuChE-Is would be efficacious and better tolerated than AChE-Is in AD. Herein, we applied innovative enzyme kinetic analyses to characterize the quantitative interaction of THFBFC with human BuChE. These provided values for the agent's IC50, together with specific new kinetic constants, such as KT50, KT1/2, RI, oKRT, oPmax, KPT and PT1/2, to aid define target concentrations for clinical translation. Additional classical kinetic parameters, including Ki, Km or Ks, kcat or Vmax and Vmi were also determined. THFBFC proved to be a potent competitive inhibitor of human BuChE and, like its isomer dihydrobenzodioxepine cymserine, is a potentially interesting AD drug candidate. © 2008 Springer-Verlag.
dc.language eng
dc.relation.isbasedon 10.1007/s00702-008-0022-y
dc.title Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis
dc.type Journal Article
dc.parent Journal of Neural Transmission
dc.journal.volume 6
dc.journal.volume 115
dc.journal.number 6 en_US
dc.publocation Wien en_US
dc.identifier.startpage 889 en_US
dc.identifier.endpage 898 en_US
dc.cauo.name SCI.Medical and Molecular Biosciences en_US
dc.conference Verified OK en_US
dc.for 1109 Neurosciences
dc.personcode 980838
dc.personcode 101972
dc.percentage 100 en_US
dc.classification.name Neurosciences en_US
dc.classification.type FOR-08 en_US
dc.edition en_US
dc.custom en_US
dc.date.activity en_US
dc.location.activity ISI:000256472400014 en_US
dc.description.keywords Acetylcholinesterase
dc.description.keywords Alzheimer's disease
dc.description.keywords Anticholinesterase
dc.description.keywords Bisnorcymserine
dc.description.keywords Butyrylcholinestrase
dc.description.keywords Cymserine
dc.description.keywords Enzyme inhibition kinetics
dc.description.keywords Tetrahydrofurobenzofuran
pubs.embargo.period Not known
pubs.organisational-group /University of Technology Sydney
pubs.organisational-group /University of Technology Sydney/Faculty of Science
pubs.organisational-group /University of Technology Sydney/Strength - Health Technologies
pubs.organisational-group /University of Technology Sydney/Strength - Health Technologies
utslib.copyright.status Closed Access
utslib.copyright.date 2015-04-15 12:17:09.805752+10
pubs.consider-herdc true
utslib.collection.history School of Medical and Molecular Sciences (ID: 341)
utslib.collection.history Closed (ID: 3)


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