Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adult male Long-Evans rats were intermittently exposed to 2450 MHz CW microwaves at an average power density of 0.5 mW/cm2 for 90 days. The resulting SAR was 0.14 W/kg (range 0.11 to 0.18 W/kg). The animals were exposed 7 h/day, 7 days/wk, for a total of 630 h in a monopole-above-ground radiation chamber while housed in Plexiglas holding cages. Daily measures of body mass and food and water intake indicated no statistically significant effects of microwave exposure. Monthly assessment of reactivity to electric footshock, levels of cholinesterase and sulfhydryl groups in blood, and 17-ketosteroids in urine revealed no reliable differences between 14 sham-exposed and 14 microwave-exposed rats. After the 90 days of exposure, seven rats, randomly chosen from each group, were assessed for open-field behavior, shuttlebox performance, and schedule-controlled (IRT schedule) lever pressing for food pellets. Statistically significant differences between microwave-exposed and sham-exposed rats were observed in shuttlebox performances and lever pressing. Post mortem measures of mass of several organs and microscopic examination of adrenal tissue revealed no differences between the two groups of animals.
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PMID:Behavioral and physiological effects of chronic 2,450-MHz microwave irradiation of the rat at 0.5 mW/cm2. 373 1

A concept for toxicity assessments based on in vitro assays of variant levels (i.e., from whole cells to isolated enzymes) is presented. Due to the complexity of organisms of different species, it is evident that no single in vitro test can represent the entire spectrum of toxic potency of chemicals, rather a carefully designed battery of tests has to be employed to account for the various targets attacked in organisms yielding the different modes of action. Cytotoxicity tests like the Neutral-Red Assay predominantly reflect non-specific toxicity, which can be modelled according to a log Pow dependent baseline QSAR. Specific toxicants (e.g., decouplers, acetylcholinesterase inhibitors or photosystem II inhibitors) may be identified based on according in vitro tests and eventually modelled by the respective mode of action related QSARs employing also, e.g., steric or polarizability descriptors to account for specific interactions. The complementation and partial replacement of in vivo (eco)toxicological testing by in vitro assays depends on two criteria: (a) the sensitivity of the tests to reliably detect environmentally relevant concentrations of toxicants and (b) the specificity of the assays to provide an unambiguous classification of toxicants by modes of action: the pattern of interaction with the various targets allows to recognize those compounds of specific effects that frequently occur as outliers in QSAR analyses.
SAR QSAR Environ Res 1995
PMID:Classification of contaminants by mode of action based on in vitro assays. 876 2

The simulated binding profiles of acetylcholine, ACh, and the inhibitor (+/-)-2,3-dihydro-5,6- dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-on e hydrochloride (E2020), 1, and some of its analogs to acetylcholinesterase, AChE, were determined using full force field energetics and allowing complete conformational flexibility in both the ligand and receptor. A new mode of binding of ACh to AChE was found which involves the carboxyl oxygen of ACh interacting with Gly 118 and 119. Multiple modes of binding of 1 and some of its analogs were found which include alignment models observed in previous more restricted modeling studies. The key ligand-receptor interactions identified, and the corresponding energetics, are consistent on a relative basis, with observed binding constants for both the individual isomers of each of the inhibitors, as well as among the inhibitors themselves. The multiple modes of binding of 1 to AChE arises from small changes in binding at a single subsite and also from multiple subsite changes. Thus, an independent subsite model for ligand-receptor binding holds for some modes of binding, but not for others. A comparison of the simulated AChE-1 (and analog inhibitors) binding models to the receptor-independent 3D-QSARs previously developed for this class of inhibitors reveals extensive mutual consistency. The findings from these two modeling studies provides greater guidelines for inhibitor design than can be realized from either one. The combined docking and 3D-QSAR studies permit a detailed understanding of the SAR of more than 100 compound 1 analog inhibitors. A simple molecular recognition model can also be gleaned from the docking studies. A cylindrical "plug" (the inhibitor) having a large dipole moment must sterically fit into a cylindrical hole (the active site gorge of AChE), the lining of which also has a large dipole moment. Our simulations suggest that the dynamic "back door" to the active site of AChE does not form a large enough opening for sufficiently long time periods so as to be an effective entrance/exit pathway.
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PMID:The simulated binding of (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]meth yl] -1H-inden-1-one hydrochloride (E2020) and related inhibitors to free and acylated acetylcholinesterases and corresponding structure-activity analyses. 889 40

Semiempirical quantum calculations were performed on a series of organophosphorus fluoridates to determine the relative reactivity for hydrolysis. This value was determined by subtracting the energy of the metastable intermediate from the energy of the stable molecule. Plotting this relative reactivity for each compound vs. its toxicity resulted in a parabolic curve with nerve agents and other similarly toxic compounds in the center. The more reactive phosphinates and less reactive phosphates were at the edges of the graph in the region of lower toxicity. The results indicate that for compounds meeting minimal structural requirements, chemical reactivity is the principal determinant of cholinesterase inhibition.
SAR QSAR Environ Res 1999
PMID:Effects of chemical reactivity of the toxicity of phosphorus fluoridates. 1049 50

In this study, we attempted to derive a comprehensive SAR picture for the class of acetylcholinesterase (AChE) inhibitors related to tacrine, a drug currently in use for the treatment of the Alzheimer's disease. To this aim, we synthesized and tested a series of 9-amino-1,2,3,4-tetrahydroacridine derivatives substituted in the positions 6 and 7 of the acridine nucleus and bearing selected groups on the 9-amino function. By means of the Hansch approach, QSAR equations were obtained, quantitatively accounting for both the detrimental steric effect of substituents in position 7 and the favorable electron-attracting effect exerted by substituents in positions 6 and 7 of the 9-amino-1,2,3,4-tetrahydroacridine derivatives. The three-dimensional (3D) properties of the inhibitors were taken into consideration by performing a CoMFA analysis on the series of AChE inhibitors made by 12 9-amino-1,2,3, 4-tetrahydroacridines and 13 11H-indeno[1,2-b]quinolin-10-ylamines previously developed in our laboratory. The alignment of the molecules to be submitted to the CoMFA procedure was carried out by taking advantage of docking models calculated for the interactions of both the unsubstituted 9-amino-1,2,3,4-tetrahydroacridine and 11H-indeno[1,2-b]quinolin-10-ylamine with the target enzyme. A highly significant CoMFA model was obtained using the steric field alone, and the features of such a 3D QSAR model were compared with the classical QSAR equations previously calculated. The two models appeared consistent, the main aspects they had in common being (a) the individuation of the strongly negative contribution of the substituents in position 7 of tacrine and (b) a tentative assignment of the hydrophobic character to the favorable effect exerted by the substituents in position 6. Finally, a new previously unreported tacrine derivative designed on the basis of both the classical and the 3D QSAR equations was synthesized and kinetically evaluated, to test the predictive ability of the QSAR models. The 6-bromo-9-amino-1,2,3,4-tetrahydroacridine was predicted to have a pIC(50) value of 7.31 by the classical QSAR model and 7.40 by the CoMFA model, while its experimental IC(50) value was equal to 0.066 (+/-0.009) microM, corresponding to a pIC(50) of 7.18, showing a reasonable agreement between predicted and observed AChE inhibition data.
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PMID:SAR of 9-amino-1,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors: synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMFA of tacrine analogues. 1082 13

The PLS variant of the MTD method (T. I. Oprea et al., SAR QSAR Environ. Res. 2001, 12, 75-92) was applied to a series of 25 acetylcholinesterase hydrolysis substrates. Statistically significant MTD-PLS models (q(2) between 0.7 and 0.8) are in agreement with previous MTD models, with the advantage that local contributions are understood beyond the occupancy/nonoccupancy interpretation in MTD. A "chemically intuitive" approach further forces MTD-PLS coefficients to assume only negative (or zero) values for fragmental volume descriptors and positive (or zero) values for fragmental hydrophobicity descriptors. This further separates the various kinds of local interactions at each vertex of the MTD hypermolecule, making this method suitable for medicinal chemistry synthesis planning.
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PMID:MTD-PLS: A PLS-based variant of the MTD method. 2. Mapping ligand-receptor interactions. Enzymatic acetic acid esters hydrolysis. 1213 84

The potent herbicide paraquat and three other analogues MPP+, MPDP+ and MPTP have a known toxicological profile linked to the ability to damage dopaminergic neurons. Other biological effects were recently addressed to this class of compounds, including the ability to interact with enzymatic targets involved in the Central Nervous System, such as the acetylcholinesterase (AChE) and the butyrylcholinesterase (BuChE). A combined molecular modelling and enzymatic study focusing onto their interaction against the AChE and BuChE is reported. The former study was performed by docking techniques using target known co-crystallographic models. The latter study was carried out by the widely adopted Ellman's method. In both studies the anti-Alzheimer FDA approved drug tacrine was used as reference inhibitor. Our results indicate that paraquat, MPTP, MPDP+ and MPP+ recognize both enzymatic cleft in a similar fashion compared to the reference inhibitor. A structure-activity correlation was found with the net charge of the ligands, indicating a major role of the electrostatic term in the recognition and inhibition of these compounds. Our data completed their enzymatic profile, added new information on the molecular mechanisms underlying their neurotoxicity useful for the rational design of new cholinesterase inhibitors.
SAR QSAR Environ Res
PMID:Molecular modelling and enzymatic studies of acetylcholinesterase and butyrylcholinesterase recognition with paraquat and related compounds. 1765 39

Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Fifteen new monooxime reactivators of acetylcholinesterase with a (E)-but-2-ene linker were developed in an effort to extend the properties of K-oxime (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203). The known reactivators (pralidoxime, HI-6, obidoxime, K075, K203) and the new compounds were tested in vitro on a model of tabun- and paraoxon-inhibited AChE. Monooxime reactivators were not able to exceed the best known compounds for tabun poisoning, but some of them did show reactivation comparable with known compounds for paraoxon poisoning. However, extensive differences were found by a SAR study for various substitutions on the non-oxime part of the reactivator molecule.
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PMID:Monooxime reactivators of acetylcholinesterase with (E)-but-2-ene linker: preparation and reactivation of tabun- and paraoxon-inhibited acetylcholinesterase. 1776 57

Protein conformational fluctuations are critical for biological functions, although the relationship between protein motion and function has yet to be fully explored. By a thorough bioinformatics analysis of cholinesterases (ChEs), we identified specific hot spots, responsible for protein fluctuations and functions, and those active-site residues that play a role in modulating the cooperative network among the key substructures. This drew the optimization of our design strategy to discover potent and reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase (hAChE and hBuChE) that selectively interact with specific protein substructures. Accordingly, two tricyclic moieties differently spaced by functionalized linkers were investigated as molecular yardsticks to probe the finest interactions with specific hot spots in the hChE gorge. A number of SAR trends were identified, and the multisite inhibitors 3a and 3d were found to be the most potent inhibitors of hBuChE and hAChE known to date.
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PMID:Exploiting protein fluctuations at the active-site gorge of human cholinesterases: further optimization of the design strategy to develop extremely potent inhibitors. 1847 18

Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Eighteen monoquaternary reactivators of acetylcholinesterase with modified side chain were developed in an effort to extend the properties of pralidoxime. The known reactivators (pralidoxime, HI-6, obidoxime, trimedoxime, methoxime) and the prepared compounds were tested in vitro on a model of tabun- and paraoxon-inhibited AChE. Monoquaternary reactivators were not able to exceed the best known compounds for tabun poisoning, but some of them did show reactivation better or comparable with pralidoxime for paraoxon poisoning. However, extensive differences were found by a SAR study for various side chains on the non-oxime part of the reactivator molecule.
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PMID:Monoquaternary pyridinium salts with modified side chain-synthesis and evaluation on model of tabun- and paraoxon-inhibited acetylcholinesterase. 1867 53


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