Inhibition of Human Cholinesterases by Drugs Used to Treat Alzheimer Disease

Darvesh, Sultan; Walsh, Ryan; Kumar, Rohit; Caines, Angela; Roberts, Sheila; MaGee, David I.; Rockwood, Kenneth; Martin, Earl

doi:10.1097/00002093-200304000-00011

Cited by 134 publications

(96 citation statements)

References 45 publications

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“…It can be seen that the second-order rate constants of the inhibition reaction (k i ) obtained by the initial rate protocol (method A) are in reasonable agreement with those calculated from the equations that describe the rate of approach to steady state and the steady state residual activity (method B). Furthermore, k i of rhAChE and hBChE determined for rivastigmine by method A were in reasonable agreement with those reported previously by the use of different experimental protocols (Bar-On et al, 2002;Darvesh et al, 2003). Thus, method A and B are satisfactory for determination of the inhibition rate constants.…”

Section: Decarbamylation Ratesupporting

confidence: 88%

The Kinetics of Inhibition of Human Acetylcholinesterase and Butyrylcholinesterase by Two Series of Novel Carbamates

Groner¹,

Ashani²,

Schorer-Apelbaum³

et al. 2007

Mol Pharmacol

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Controlled inhibition of brain acetyl-and butyrylcholinesterases (AChE and BChE, respectively) and of monoamine oxidase-B (MAO-B) may slow neurodegeneration in Alzheimer's and Parkinson's diseases. It was postulated that certain carbamate esters would inhibit AChE and BChE with the concomitant release in the brain of the OH-derivatives of rasagiline or selegiline that can serve as inhibitors of MAO-B and as antioxidants. We conducted a detailed in vitro kinetic study on two series of novel N-methyl, N-alkyl carbamates and compared them with rivastigmine, a known anti-Alzheimer drug. The rates of carbamylation (k i ) and decarbamylation (k r ) of recombinant human AChE were mainly determined by the size of the N-alkyl substituent and to a lesser extent by the nature of the leaving group. k i was highest when the alkyl was methyl, hexyl, cyclohexyl, or an aromatic substituent and lowest when it was ethyl. This suggested that k i depends on a delicate balance between the length of the residue and its degree of freedom of rotation. By contrast, presumably because of its wider gorge, inhibition of human BChE was less influenced by the size of the alkyl group and more dependent on the structure of the leaving group. The data show how the degree of enzyme inhibition can be manipulated by structural changes in the N-methyl, N-alkyl carbamates and the corresponding leaving group to achieve therapeutic levels of brain AChE, BChE, and MAO-B inhibition.

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Section: Decarbamylation Ratesupporting

confidence: 88%

The Kinetics of Inhibition of Human Acetylcholinesterase and Butyrylcholinesterase by Two Series of Novel Carbamates

Groner¹,

Ashani²,

Schorer-Apelbaum³

et al. 2007

Mol Pharmacol

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“…Notably, the pharmacological features of physostigmine donepezil are slightly different, and could form a basis for differences in behavioral effects. For example, physostigmine inhibits both acetylcholinesterase and butylcholinesterase, while donepezil inhibits only acetylcholinesterase (Darvesh, et al, 2003). Moreover, physostigmine but not donepezil is a modulator at the nicotinic acetylcholine receptor (Storch, et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease

Dong¹,

Csernansky

Martin³

et al. 2005

Psychopharmacology

104

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Rationale: Acetylcholinesterase inhibitors are widely used for the treatment of patients with Alzheimer's disease (AD). However, the relationship between the capacity of such drugs to ameliorate the symptoms of AD and their ability to alter the underlying disease process is not well understood. Transgenic mice that overexpress the human form of amyloid precursor protein and develop deposits of b-amyloid (Ab) and behavioral deficits during adulthood are useful for investigating this question. Objectives: The effects of administration of two acetylcholinesterase inhibitors, physostigmine and donepezil, on Ab plaque formation and memory-related behaviors were investigated in the Tg2576 transgenic mouse model of AD. At 9-10 months of age, Tg2576 transgenic (Tg(+)) mice develop Ab plaques and impairments on paradigms related to learning and memory as compared to transgene negative (Tg(-)) mice. Methods: Beginning at 9 months of age, increasing doses of physostigmine (0.03, 0.1, and 0.3mg/kg), donepezil (0.1, 0.3 and 1.0mg/kg) or saline were administered over six weeks to cohorts of Tg(+) and Tg(-) mice. Performance on tests of spatial reversal learning and fear conditioning was evaluated at each drug dose throughout the period of drug administration. After drug administration was completed, the animals were sacrificed and Ab plaque number was quantified. Results: Administration of physostigmine and donepezil improved deficits in contextual and cued memory in Tg(+) mice so that their behaviors became more similar to Tg(-) mice. However, administration of physostigmine and donepezil tended to improve cued memory and deficits in spatial learning in both Tg(+) and Tg(-) mice. Physostigmine administration demonstrated more prominent effects in improving contextual memory than donepezil, while donepezil was more effective than physostigmine in improving deficits in the acquisition of the spatial memory paradigm. Administration of neither drug altered the deposition of Aß plaques. Conclusions: These studies suggest that acetylcholinesterase inhibitors can ameliorate memory deficits in Tg(+) mice without necessarily altering the deposition of Aß plaques. Tg2576 mice may be useful as an animal model to further investigate the mechanisms by which aceytlcholinesterase inhibitors improve cognitive deficits in patients with AD.

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“…These findings may be seen as a reason for reinvestigating possible interactions of melatonin with the acylcholinesterases. In this context, it may be briefly noted that the brain AAAs have recently, and somehow unexpectedly, re-gained some interest after they were shown to be inhibited by several investigational anti-Alzheimer drugs considered for human treatment [20,22,100]. With regard to the attempts of antagonizing Alzheimer's disease by melatonin [85,95,130,131], this possibility may be kept in mind, although melatonin exhibits numerous other properties of interest in this neurodegenerative disorder.…”

Section: Melatonin Deacetylationmentioning

confidence: 99%

Melatonin Metabolism in the Central Nervous System

Hardeland¹

2010

106

108

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Abstract:The metabolism of melatonin in the central nervous system is of interest for several reasons. Melatonin enters the brain either via the pineal recess or by uptake from the blood. It has been assumed to be also formed in some brain areas. Neuroprotection by melatonin has been demonstrated in numerous model systems, and various attempts have been undertaken to counteract neurodegeneration by melatonin treatment. Several concurrent pathways lead to different products. Cytochrome P 450 subforms have been demonstrated in the brain. They either demethylate melatonin to Nacetylserotonin, or produce 6-hydroxymelatonin, which is mostly sulfated already in the CNS. Melatonin is deacetylated, at least in pineal gland and retina, to 5-methoxytryptamine. N 1 -acetyl-N 2 -formyl-5-methoxykynuramine is formed by pyrrole-ring cleavage, by myeloperoxidase, indoleamine 2,3-dioxygenase and various non-enzymatic oxidants. Its product, N 1 -acetyl-5-methoxykynuramine, is of interest as a scavenger of reactive oxygen and nitrogen species, mitochondrial modulator, downregulator of cyclooxygenase-2, inhibitor of cyclooxygenase, neuronal and inducible NO synthases. Contrary to other nitrosated aromates, the nitrosated kynuramine metabolite, 3-acetamidomethyl-6-methoxycinnolinone, does not re-donate NO. Various other products are formed from melatonin and its metabolites by interaction with reactive oxygen and nitrogen species. The relative contribution of the various pathways to melatonin catabolism seems to be influenced by microglia activation, oxidative stress and brain levels of melatonin, which may be strongly changed in experiments on neuroprotection. Many of the melatonin metabolites, which may appear in elevated concentrations after melatonin administration, possess biological or pharmacological properties, including N-acetylserotonin, 5-methoxytryptamine and some of its derivatives, and especially the 5-methoxylated kynuramines.

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Inhibition of Human Cholinesterases by Drugs Used to Treat Alzheimer Disease

Cited by 134 publications

References 45 publications

The Kinetics of Inhibition of Human Acetylcholinesterase and Butyrylcholinesterase by Two Series of Novel Carbamates

The Kinetics of Inhibition of Human Acetylcholinesterase and Butyrylcholinesterase by Two Series of Novel Carbamates

Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease

Melatonin Metabolism in the Central Nervous System

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