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

  • Alzheimer's Disease and Related Disorders - Original Article
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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 K T50, K T1/2, R I, o K RT, o P max, K PT and PT1/2, 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.

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Scheme 1

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Abbreviations

ACh:

Acetylcholine

AChE:

Acetylcholinesterase

AChE-Is:

Acetylcholinesterase inhibitors

AD:

Alzheimer’s disease

APP:

Amyloid-β precursor protein

Aβ:

Amyloid-β peptide

BuChE:

Butyrylcholinesterase

BuSCh:

Butyrylthiocholine iodide

BuChE-Is:

Butyrylcholinesterase inhibitors

ChEs:

Cholinesterases

ChE-Is:

Cholinesterase inhibitors

CNS:

Central nervous system

FAD:

Familial Alzheimer’s disease

THFBFC:

Tetrahydrofurobenzofuran cymserine

K PT :

Preincubation time constant

K T50 :

Concentration of inhibitor doubles K T1/2

o K RT :

Overall rate of inhibition constant

P PC :

Concentration of inhibitor doubles pseudo P max

o P max :

Overall maximum product concentration

K T1/2 :

Time required for half V max;

PT1/2 :

Preincubation time required for half ν;

R I :

Rate of IC50

RβA:

Reflective binding activity

K i :

Inhibition constant

K s :

Substrate constant

K m :

Michaelis-Menten constant

k cat :

Catalytic constant

V max :

Apparent maximal activity

V mi :

V maxi

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Acknowledgments

This research was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.

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Authors and Affiliations

  1. Department of Medical and Molecular BioSciences, Faculty of Science, University of Technology Sydney, PO Box 123, Broadway, Sydney, NSW, 2007, Australia

    Mohammad A. Kamal, Xianqin Qu & Yi Tan

  2. Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Gerontology Research Center, Room 4B02, 5600 Nathan Shock Drive, Baltimore, MD, 21224, USA

    Qian-sheng Yu, David Tweedie, Harold W. Holloway, Yazhou Li & Nigel H. Greig

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  1. Mohammad A. Kamal
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  2. Xianqin Qu
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Correspondence to Mohammad A. Kamal or Nigel H. Greig.

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Kamal, M.A., Qu, X., Yu, Qs. et al. Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis. J Neural Transm 115, 889–898 (2008). https://doi.org/10.1007/s00702-008-0022-y

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