title: Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis.
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 IC(50), together with specific new kinetic constants, such as K (T50), K (T1/2), R (I), (o)K (RT), (o)P(max), K(PT) and PT(1/2), to aid define target concentrations for clinical translation. Additional classical kinetic parameters, including K(i), K(m)or K(s), k(cat) or V(max) and V (mi) 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.
authors.affiliation: Department of Medical and Molecular BioSciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia. Mohammad.Kamal@uts.edu.au
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Kamal
authors.forename: Xianqin
authors.initials: X
authors.lastname: Qu
authors.forename: Qian-Sheng
authors.initials: QS
authors.lastname: Yu
authors.forename: David
authors.initials: D
authors.lastname: Tweedie
authors.forename: Harold W
authors.initials: HW
authors.lastname: Holloway
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology*; D001667:Binding, Competitive / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000097:blood / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005663:Furans / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D044967:Serum / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D005663:Furans; C509735:cymserine; C531991:tetrahydrofurobenzofuran cymserine; D010830:Physostigmine; D002091:Butyrylcholinesterase