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. 2013 May;11(3):315-35.
doi: 10.2174/1570159X11311030006.

Acetylcholinesterase inhibitors: pharmacology and toxicology

Mirjana B Colović  1 , Danijela Z Krstić, Tamara D Lazarević-Pašti, Aleksandra M Bondžić, Vesna M Vasić
Affiliations

Acetylcholinesterase inhibitors: pharmacology and toxicology

Mirjana B Colović et al. Curr Neuropharmacol. 2013 May.

Abstract

Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer's disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases.

Keywords: Acetylcholine; Alzheimer’s disease drugs; acetylcholinesterase; carbamates; detoxification; irreversible inhibitors; organophosphates; reversible inhibitors..

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Figures

Fig. (1)
Fig. (1)
Mechanism of AChE action in neurotransmission.
Fig. (2)
Fig. (2)
Schematic representation of AChE binding sites.
Fig. (3)
Fig. (3)
Mechanism of ACh hydrolysis catalyzed by AChE.
Fig. (4)
Fig. (4)
Selected reversible AChE inhibitors in pharmacotherapy of AD.
Fig. (5)
Fig. (5)
General chemical structure of biologically active carbamates.
Fig. (6)
Fig. (6)
Mechanism of AChE inhibition induced by OPs; reactivation, spontaneous hydrolysis, and aging of the phosphorylated enzyme.
Fig. (7)
Fig. (7)
Selected carbamate insecticides.
Fig. (8)
Fig. (8)
Selected carbamates being applied as herbicides and fungicides.
Fig. (9)
Fig. (9)
Structural formula of physostigmine and pyridostigmine.
Fig. (10)
Fig. (10)
General structural formula of OPs.
Fig. (11)
Fig. (11)
(a). Progressive development of inhibition produced by reaction of AChE with different concentrations of diazoxon plotted as semi logarithmic curve in accordance with Equation (1). Diazoxon concentrations (in mol/l): (1) 2 × 10-8, (2) 3 × 10-8, (3) 5 × 10-8, (4) 7.5 × 10-8, (5) 1 × 10-7, and (6) 2 × 10-7. Reproduced from [90]. (b). The dependence of kapp upon the concentration of diazoxon (1), chlorpyrifos-oxon (2) and chlorpyrifos ((3), inset) plotted as reciprocals in accordance with Equation (2). Reproduced from [90].
Fig. (12)
Fig. (12)
Selected OP insecticides.
Fig. (13)
Fig. (13)
Selected nerve agents.
Fig. (14)
Fig. (14)
Pharmacologically important OPs.
Fig. (15)
Fig. (15)
Frequently used drugs for symptomatic treatment of OP intoxication.
Fig. (16)
Fig. (16)
Regeneration of inhibited AChE activity by oxime reactivators.
Fig. (17)
Fig. (17)
Commercially available oxime reactivators of AChE activity.
Fig. (18)
Fig. (18)
Mechanism of CESs catalyzed hydrolysis of carboxyl esters.
Fig. (19)
Fig. (19)
CESs catalyzed hydrolysis of carbamate insecticides.
Fig. (20)
Fig. (20)
Inhibition of B-esterases by OPs.
Fig. (21)
Fig. (21)
OPs hydrolysis catalyzed by known PTEs: DFPase and paraoxonase.
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