Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Screen-printing technology for electrode fabrication enables construction of amperometric devices suitable for combination of several enzyme electrodes. To develop a biosensor array for characterisation of wastewaters, tyrosinase and horseradish peroxidase (HRP) or cholinesterase-modified electrodes were combined on the same array. The behaviour of the tyrosinase-modified electrode in the presence of hydrogen peroxide (required co-substrate for the HRP-modified electrode) and acetylthiocholine chloride (required co-substrate for cholinesterase) was studied. Performance of bi-enzyme biosensor arrays in the batch mode and in the flow-injection system are discussed.
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PMID:Screen-printed multienzyme arrays for use in amperometric batch and flow systems. 1285 95

Fluoride ion is a reversible inhibitor of human butyrylcholinesterase (HuBChE) that is a viable drug candidate against organophosphates (OPs) toxicity. Since large numbers of communities in many countries are occasionally exposed to relatively high amount of fluoride, its effect on the kinetics of inhibition of HuBChE by OPs was investigated. In saline phosphate, pH 7.4, fluoride in the lower millimolar range significantly slowed the inhibition of HuBChE by paraoxon, DFP, echothiophate, soman, sarin, and VX. The kinetics of the inhibition was found consistent with the formation of a reversible fluoride-HuBChE complex that is at least 25-fold less active towards phosphorylation or phosphonylation than the free enzyme. Heat inactivation experiments indicate that the binding of fluoride to HuBChE probably involves enhanced cross-domain interaction via hydrogen bonds formation that may decrease enzyme activity. In spite of distinct structural differences among the OP used, the dissociation constants of the fluoride-HuBChE reversible complex varied over a narrow range (KF, 0.31-0.70 mM); however, KF in human plasma increased to 2.75-3.40 mM. 19F-NMR spectroscopy revealed that fluoride ion is complexed to plasma components, an observation that explains in part the apparent increase in KF. Results suggest that an estimate of the relative decrease in the rate of OPs sequestration in presence of fluoride can be obtained from the fraction of the free HuBChE (1 + [F]/K(F))(-1). Considering KF values in human plasma, it is concluded that the scavenging efficacy of OPs by HuBChE is not compromised by the normal concentration range of circulating fluoride ions.
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PMID:The effect of fluoride on the scavenging of organophosphates by human butyrylcholinesterase in buffer solutions and human plasma. 1472 83

Tacrine, a cholinesterase inhibitor, was approved for the treatment of Alzheimer's disease. Oxidative metabolism of tacrine occurs by CYP1A-catalyzed hydroxylation. In rats, it was observed that the area under the curve (AUC) of the second oral dose was consistently higher than the AUC after the first oral dose, which was not due to the accumulation of the drug in the plasma from the first dose. This finding suggested inhibition of the enzyme during metabolism or inhibition by a metabolite. The inhibitory mechanism was studied in liver and intestinal microsomes prepared from 3-methylcholanthrene-treated rats and with recombinant CYP1A1 and CYP1A2. Preincubation of CYP1A2 with tacrine and NADPH revealed a time-dependent inhibition of 7-ethoxyresorufin O-de-ethylation with a K(i) of 1.94 microM and a k(inact) of 0.091 min(-1). No time-dependent inhibition was observed with CYP1A1 or with 1-hydroxytacrine or 2-hydroxytacrine. Tacrine metabolism catalyzed by CYP1A was also carried out, and the partition ratio was estimated to be 22. A modified Michaelis-Menten equation involving mechanism-based inhibition was derived and used to analyze the data. Reasonable parameter fits were obtained indicating that this equation is suitable to describe metabolism data when the substrate is a mechanism-based inhibitor of the enzyme. The probable inactivation mechanism involves either hydrogen atom abstraction to produce a carbon-centered radical intermediate at the benzylic position or insertion of OH(+) into a C-H bond with subsequent loss of water to produce a carbocation. Rapid rearrangement of the carbocation or radical and subsequent covalent binding of the tacrine moiety would result in enzyme inactivation.
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PMID:Inhibition of murine cytochrome P4501A by tacrine: in vitro studies. 1525 5

Degeneration of nigrostriatal dopamine neurons and cholinergic cortical neurones are the main pathological features of Parkinson's disease (PD) and for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB), respectively. Many PD and DLB subjects have dementia and depression resulting from possible degeneration of cholinergic and noradrenergic and serotonergic neurons. On the other hand, AD patients may also develop extrapyramidal features as well as depression. In both PD and AD there is, respectively, accumulation of iron within the melanin containing dopamine neurons of pars compacta and with in the plaques and tangle. It has been suggested that iron accumulation may contribute to the oxidative stress induced apoptosis reported in both diseases. This may result from increased glia hydrogen peroxide producing monoamine oxidase (MAO) activity that can generate of reactive hydroxyl radical formed from interaction of iron and hydrogen peroxide. We have therefore prepared a series of novel bifunctional drugs from the neuroprotective-antiapoptotic antiparkinson monoamine oxidase B inhibitor, rasagiline, by introducing a carbamate cholinesterase (ChE) inhibitory moiety into it. Ladostigil (TV-3326, N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), has both ChE and MAO-AB inhibitory activity, as potential treatment of AD and DLB or PD subjects with dementia Being a brain selective MAO-AB inhibitor it has limited potentiation of the pressor response to oral tyramine and exhibits antidepressant activity similar to classical non-selective MAO inhibitor antidepressants by increasing brain serotonin and noradrenaline. Ladostigil inhibits brain acetyl and butyrylcholinesterase in rats and antagonizes scopolamine-induced inhibition of spatial learning. Ladostigil like MAO-B inhibitor it prevents MPTP Parkinsonism in mice model and retains the in vitro and in vivo neuroprotective activity of rasagiline. Ladostigil, rasagiline and other propargylamines have been demonstrated to have neuroprotective activity in several in vitro and in vivo models, which have been shown be associated with propargylamines moiety, since propargylamines itself possess these properties. The mechanism of neuroprotective activity has been attributed to the ability of propargylamines-inducing the antiapoptotic family proteins Bcl-2 and Bcl-xl, while decreasing Bad and Bax and preventing opening of mitochondrial permeability transition pore. Iron accumulates in brain regions associated with neurodegenerative diseases of PD, AD, amyotrophic lateral sclerosis and Huntington disease. It is thought to be involved in Fenton chemistry oxidative stress observed in these diseases. The neuroprotective activity of propargylamines led us to develop several novel bifunctional iron chelator from our prototype brain permeable iron chelators, VK-28, possessing propargylamine moiety (HLA-20, M30 and M30A) to iron out iron from the brain. These compounds have been shown to have iron chelating and monoamine oxidase A and B selective brain inhibitory and neuroprotective-antiapoptotic actions.
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PMID:Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases. 1562 Dec 13

An isocratic, reversed-phase liquid chromatographic (RPLC) method was developed for the quantitative determination of Rivastigmine hydrogen tartrate, a cholinesterase inhibitor in bulk drugs and in pharmaceutical dosage forms. The developed method is also applicable for the related substance determination of Rivastigmine hydrogen tartrate in bulk drugs. The chromatographic separation was achieved on a Waters X Terra RP18 (250 mm x 4.6 mm, 5 microm) column using aqueous 0.01 M sodium-1-heptane sulphonate (pH: 3.0 with dilute phosphoric acid)-acetonitrile (72:28, v/v) as a mobile phase. The chromatographic resolution between Rivastigmine and its potential impurity, namely (S)-3-(1-dimethylaminoethyl) phenol (Imp 1) was found to be greater than four. Forced degradation studies were performed for Rivastigmine hydrogen tartrate bulk drug using acid (0.5 N hydrochloric acid), base (0.5 N sodium hydroxide), oxidation (3% hydrogen peroxide), heat (60 degrees C) and UV light (254 nm). No degradation was observed for Rivastigmine hydrogen tartrate except in base hydrolysis and the formed degradation product was found to be Imp 1. The mass balance of Rivastigmine hydrogen tartrate was close to 100 in all the stress conditions. The limit of detection (LOD) and limit of quantification (LOQ) of Imp 1 were found to be 100 and 300 ng/ml, respectively, for 10 microl injection volume. The percentage recovery of Imp 1 in bulk drug sample was ranged from 95.2 to 104.3. The active pharmaceutical ingredient was extracted from its finished dosage form (capsule) using water. The percentage recovery of Rivastigmine hydrogen tartrate was ranged from 99.2 to 101.3 and 98.6 to 101.5 in bulk and pharmaceutical formulation samples, respectively. Rivastigmine hydrogen tartrate sample solution and mobile phase were found to be stable for at least 48 h. The developed method was validated with respect to linearity, accuracy, precision, robustness and forced degradation studies prove the stability indicating power of the method.
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PMID:A stability indicating LC method for rivastigmine hydrogen tartrate. 1566 43

A new and accurate chiral liquid chromatographic method was developed for the enantiomeric resolution of Rivastigmine hydrogen tartarate, (-)S-N-ethyl-3-[(1-dimethyl-amino)ethyl]-N-methylphenyl-carbamate hydrogen tartarate, a cholinesterase inhibitor in bulk drugs. The enantiomers of Rivastigmine hydrogen tartarate were baseline resolved on a Chiralcel OD-H (250 mm x 4.6 mm, 5 microm) column using a mobile phase system containing hexane: isopropanol: trifluoroacetic acid (80:20:0.2, v/v/v). The resolution between the enantiomers was not less than four and interestingly distomer was eluted prior to eutomer in the developed method. The presence of trifluoroacetic acid in the mobile phase has played an important role in enhancing chromatographic efficiency and resolution between the enantiomers. The developed method was extensively validated and proved to be robust. The limit of detection and limit of quantification of (R)-enantiomer were found to be 500 and 1500 ng/ml, respectively for 10 microl injection volume. The percentage recovery of (R)-enantiomer was ranged from 95.2 to 104.3 in bulk drug samples of Rivastigmine hydrogen tartarate. Rivastigmine hydrogen tartarate sample solution and mobile phase were found to be stable for at least 48 h. The proposed method was found to be suitable and accurate for the quantitative determination of (R)-enantiomer in bulk drugs. Chiralcel OJ-H column can also be used as an alternative for the above purpose.
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PMID:A validated chiral liquid chromatographic method for the enantiomeric separation of Rivastigmine hydrogen tartarate, a cholinesterase inhibitor. 1592 25

The alkaloid juliflorine (1) from Prosopis juliflora inhibited acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8) enzymes in a concentration-dependent fashion with IC50 values 0.42 and 0.12 microM, respectively. Lineweaver-Burk as well as Dixon plots and their secondary replots indicated that the nature of inhibition was purely of non-competitive type with Ki values 0.4 and 0.1 microM, against AChE and BChE, respectively. By molecular docking studies compound 1 was found to be ideally spaced inside the aromatic gorge of AChE with rings A/B remaining at the top and rings C/D penetrating deep into the gorge, that might be due to the greater hydrophobicity of rings C/D as compared to rings A/B, allowing their simultaneous interaction with the peripheral anionic and quaternary ammonium-binding sites. The 1-AChE complex was found to be stabilized by hydrophobic contacts, hydrogen bonding, and pi-pi stacking between the compound 1 and amino acid residues of the aromatic gorge of AChE. Amino acid residues Tyr70, Asp72, Tyr121, Trp279, and Tyr334 of the peripheral anionic site (PAS) of AChE were found to be exclusively involved in the hydrophobic contacts with compound 1 that might be responsible for the competitive mode of inhibition. Compound 1 also showed dose-dependent (30-500 microg/mL) spasmolytic and Ca2+-channel blocking activities in isolated rabbit jejunum preparations. The cholinesterase inhibitory potential along with calcium-channel blocking activity of compound 1 and safe profile in human neutrophils viable assay could make it a possible drug candidate for Alzheimer's disease.
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PMID:Juliflorine: a potent natural peripheral anionic-site-binding inhibitor of acetylcholinesterase with calcium-channel blocking potential, a leading candidate for Alzheimer's disease therapy. 1602 92

Phenyl carbamates are used to treat Alzheimer's disease. These compounds inhibit acetylcholinesterase and butyrylcholinesterase. The goal of this work was to determine the chemical characteristics of ortho substituents that make some carbamates better inhibitors of butyrylcholinesterase than of acetylcholinesterase, cholesterol esterase, and lipase. The inhibition constants, Ki, Ki', kc, and ki were measured for nine different carbamates. The values were plotted according to Hammett, Taft-Kutter-Hansch, and Swan-Lupton to obtain constants that correlated the chemical nature of the substituents with inhibition potency. It was found that the negative charges of tetrahedral intermediates were more stabilized by ortho electron-withdrawing substituents of the inhibitors in butyrylcholinesterase than in acetylcholinesterase. This result confirmed formation of 3-pronged hydrogen bonds for the oxyanion hole of butyrylcholinesterase and 2-pronged hydrogen bonds for the oxyanion hole of acetylcholinesterase. Furthermore, it was found that ortho electron-donating substituents of the inhibitors accelerated inhibition of butyrylcholinesterase by ortho polar effects. Conformations of enzyme-inhibitor tetrahedral intermediates for butyrylcholinesterase were different from those for acetylcholinesterase and cholesterol esterase; ortho substituents in the tetrahedral intermediates were located far from the negatively charged carbonyl oxygens in butyrylcholinesterase, but close to the negatively charged carbonyl oxygens in acetylcholinesterase and cholesterol esterase. In conclusion, electron-donating substituents in the ortho position were better inhibitors of butyrylcholinesterase than acetylcholinesterase, while electron-withdrawing substituents were better inhibitors of acetylcholinesterase.
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PMID:Ortho effects for inhibition mechanisms of butyrylcholinesterase by o-substituted phenyl N-butyl carbamates and comparison with acetylcholinesterase, cholesterol esterase, and lipase. 1602 4

The pressure behavior of proteins may be summarized as a the pressure-induced disordering of their structures. This thermodynamic parameter has effects on proteins that are similar but not identical to those induced by temperature, the other thermodynamic parameter. Of particular importance are the intermolecular interactions that follow partial protein unfolding and that give rise to the formation of fibrils. Because some proteins do not form fibrils under pressure, these observations can be related to the shape of the stability diagram. Weak interactions which are differently affected by hydrostatic pressure or temperature play a determinant role in protein stability. Pressure acts on the 2 degrees, 3 degrees and 4 degrees structures of proteins which are maintained by electrostatic and hydrophobic interactions and by hydrogen bonds. We present some typical examples of how pressure affects the tertiary structure of proteins (the case of prion proteins), induces unfolding (ataxin), is a convenient tool to study enzyme dissociation (enolase), and provides arguments to understand the role of the partial volume of an enzyme (butyrylcholinesterase). This approach may have important implications for the understanding of the basic mechanism of protein diseases and for the development of preventive and therapeutic measures.
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PMID:The powerful high pressure tool for protein conformational studies. 1608 57

The withanolides 1-3 and 4-5 isolated from Ajuga bracteosa and Withania somnifera, respectively, inhibited acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8) enzymes in a concentration-dependent fashion with IC50 values ranging between 20.5 and 49,2 microm and 29.0 and 85.2 microm for AChE and BChE, respectively. Lineweaver-Burk as well as Dixon plots and their secondary replots indicated that compounds 1, 3, and 5 are the linear mixed-type inhibitors of AChE, while 2 and 4 are non-competitive inhibitors of AChE with K(i) values ranging between 20.0 and 45.0 microm. All compounds were found to be non-competitive inhibitors of BChE with K(i) values ranging between 27.7 and 90.6 microm. Molecular docking study revealed that all the ligands are completely buried inside the aromatic gorge of AChE, while compounds 1, 3, and 5 extend up to the catalytic triad. A comparison of the docking results showed that all ligands generally adopt the same binding mode and lie parallel to the surface of the gorge. The superposition of the docked structures demonstrated that the non-flexible skeleton of the ligands always penetrates the aromatic gorge through the six-membered ring A, allowing their simultaneous interaction with more than one subsite of the active center. The affinity of ligands with AChE was found to be the cumulative effects of number of hydrophobic contacts and hydrogen bonding. Furthermore, all compounds also displayed dose-dependent (0.005-1.0 mg/mL) spasmolytic and Ca2+ antagonistic potentials in isolated rabbit jejunum preparations, compound 4 being the most active with an ED50 value of 0.09 +/- 0.001 mg/mL and 0.22 +/- 0.01 microg/mL on spontaneous and K+ -induced contractions, respectively. The cholinesterase inhibitory potential along with calcium antagonistic ability and safe profile in human neutrophil viability assay could make compounds 1-5 possible drug candidates for further study to treat Alzheimer's disease and associated problems.
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PMID:Withanolides, a new class of natural cholinesterase inhibitors with calcium antagonistic properties. 1610 94


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