Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tacrine-based AChE and BuChE inhibitors were designed by investigating the topology of the active site gorge of the two enzymes. The homobivalent ligands characterized by a nitrogen-bridged atom at the tether level could be considered among the most potent and selective cholinesterase inhibitors described to date. The nitrogen-containing homobivalent ligands 3e,g and the sulfur-containing 3h validated the hypothesis of extra sites of interaction in the AChE and BuChE active site gorges.
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PMID:Specific targeting of acetylcholinesterase and butyrylcholinesterase recognition sites. Rational design of novel, selective, and highly potent cholinesterase inhibitors. 1250 52

Continuing our studies on polyamine-based compounds of potential interest in the field of Alzheimer's disease therapeutics, we investigated the structure-activity relationships (SAR) of a lead compound (caproctamine, 3) identified in a previous work. In particular, we varied the substituents on the phenyl ring and on the nitrogen functions (both the amine and the amide), and studied the effects of such modifications on the inhibitory potency against isolated acetyl- and butyryl-cholinesterase (AChE and BChE). Moreover, the ability of selected compounds to reverse the d-tubocurarine-induced neuromuscular blockade and their antagonism toward muscarinic M(2) receptors in guinea pig left atrium were assayed. The most interesting SAR result was the identification of a relationship between the electronic characteristics of 2-substituents (measured by pK(a)) and the AChE inhibitory potency (pIC(50)) of tertiary amine compounds 6-12, which was confirmed by the invariance of the pIC(50) values of the corresponding methiodide derivatives 14-20. With regard to the biological profile, the most interesting compound was the N-ethyl-analogue of caproctamine (9), that showed pIC(50) values of 7.73 (+/-0.02) and 5.65 (+/-0.03) against AChE and BChE, respectively. The ability to increase the acetylcholine level was maintained in the functional assay (pAI(50) for reversing the neuromuscular blockade was 6.45 (+/-0.07)), as well as the ability to antagonize the M(2) receptors (pK(b) = 5.65 (+/-0.06)). Moreover, 9 showed a long duration of action as AChE inhibitor, an useful property in view of a possible development of this compound as a therapeutic agent.
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PMID:Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 2. Role of the substituents on the phenyl ring and nitrogen atoms of caproctamine. 1262 72

Within the pulmonary epithelial lining layer (ELF), antioxidants such as ascorbic acid (AH(2)) and glutathione (GSH) react with inhaled nitrogen dioxide ((*)NO(2)) to produce reactive oxygen species (ROS) that induce cellular oxidation. Because the ELF contains unsaturated fatty acids (UFA), which potentially react with (*)NO(2) and/or the antioxidant-derived ROS, we studied the influence of aqueous phase model UFA [egg phosphatidylcholine (EggPC) liposomes] on exposure-induced oxidation and nitration of membranes. Our lung surface model used gas phase (*)NO(2) exposures of immobilized red cell membranes (RCM) overlaid with defined aqueous phases. Acetyl cholinesterase (AChE) activity, TBARS, and 3-nitrotyrosine (3-NT) were used to assess protein and lipid oxidation and RCM nitration, respectively. During (*)NO(2) exposure, AH(2) and GSH induced AChE loss and TBARS, which were unchanged with buffer only. Exposures of EggPC generated extensive TBARS but not AChE loss; addition of AH(2)/GSH to EggPC resulted in smaller AChE declines and fewer TBARS. 3-NT formation occurred with or without EggPC, low concentration antioxidants, SOD, catalase, or DTPA, but was inhibitable by desferrioxamine or high antioxidant concentrations. The data suggest that reaction/diffusion limitations govern (*)NO(2) distribution, that (*)NO(2) per se directly nitrates tyrosine residues within hydrophobic regions, and that the induction of secondary oxidative processes is dependent on nonlinear relationships among (*)NO(2) flux rates, antioxidant concentrations, and diffusivity of secondary reactive species.
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PMID:Influence of epithelial lining fluid lipids on NO(2)-induced membrane oxidation and nitration. 1263 49

We have previously described a scoring system for patients undergoing hemopoietic stem cell transplantation (HSCT) based on day +7 blood urea nitrogen (BUN) and serum bilirubin levels. We have revised that scoring system using a formal multivariate approach based on a training phase (305 patients) and a validation phase (217 patients). Day +7 BUN, serum cholinesterase (CHE), total proteins (TP), gamma glutamyl transferase (gammaGT), donor type and cell dose at transplant were included in the new score. The score distribution identified three groups of patients in the training set (<25, 25-75, >75 percentile of the score) which were classified as low, intermediate and high risk. Their actuarial risk of transplant-related mortality (TRM) at 6 years was, respectively, 12, 38 and 60%. In the validation set the 6 year actuarial TRM was, respectively, 15, 40 and 69%. High risk patients had more graft-versus-host disease (GvHD) (P <0.0001) and lower platelet counts (P <0.0001). This study confirms that GvHD and TRM can be predicted on day +7 after HSCT: pre-emptive GvHD therapy may be one option for high-risk patients and is being tested in a prospective randomized trial. The score for single patients can be calculated on the web site http://213.26.110.20/lrm/day_seven_score.html.
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PMID:A revised day +7 predictive score for transplant-related mortality: serum cholinesterase, total protein, blood urea nitrogen, gamma glutamyl transferase, donor type and cell dose. 1283 86

Recently, several bis-pyridiniumaldoximes linked by a variable-length alkylene chain were rationally designed in our laboratories as cholinesterase reactivators. Extensive in vitro tests of these oximes with acetylcholinesterase inhibited by two different organophosphate agents, echothiophate and diisopropylfluorophosphate, revealed one compound with particularly good reactivation kinetics and affinity for phosphorylated acetylcholinesterase (AChE). This compound, designated "ortho-7", with a heptylene chain bridging two aldoximes ortho to a pyridinium ring nitrogen, was chosen for detailed comparison with the classic reactivator pyridine-2-aldoxime methochloride (2-PAM). In vitro, ortho-7 reactivated AChE selectively, without restoring activity of the related enzyme butyrylcholinesterase (BChE). For in vivo studies, rats were injected with ortho-7 or 2-PAM before or after organophosphate exposure, and the activities of AChE and BChE were determined at multiple intervals in blood and solid tissues. Ortho-7 behaved nearly as well in the animal as in vitro, reactivating AChE to the same extent as 2-PAM in all peripheral tissues studied (serum, red blood cell, and diaphragm), but at doses up to 100-fold smaller. Like other oxime reactivators, ortho-7 did not reactivate brain AChE after systemic administration. Nonetheless, this agent could be useful in combination therapy for organophosphate exposure, and it may provide a platform for development of additional, even more effective reactivators.
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PMID:Cholinesterase reactivation in vivo with a novel bis-oxime optimized by computer-aided design. 1289 43

Frog skin cholinesterase is largely of the serum (pseudocholinesterase) type. For whole skin, the activity at 10(-1) AcChCl is 4.9 microl./mg. N/hr. Tela subcutanea isolated by dissection exhibits an activity of 65 microl./mg. N/hr. at 10(-1) AcChCl. Since about one-tenth of the nitrogen of the skin is located in the tela subcutanea, it is estimated that more than 90 per cent of the enzyme is associated with this tissue layer.
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PMID:The characterization and localization of frog skin cholinesterase. 1356 3

Searle, Barbara W. (Stanford University School of Medicine, Palo Alto, Calif.) and Avram Goldstein. Mutation to neostigmine resistance in a cholinesterase-containing Pseudomonas. J. Bacteriol. 83:789-796. 1962.-In a strain of Pseudomonas fluorescens containing an inducible cholinesterase, the activity of that enzyme is rate-limiting for growth when acetyl-choline is the sole source of carbon or nitrogen. Under these circumstances, neostigmine, a cholinesterase inhibitor, becomes a growth inhibitor.A neostigmine-resistant mutant was isolated, and the properties of its cholinesterase were compared with those of the wild-type enzyme. There were no differences in penetration of cells by inhibitor, rate of enzyme-inhibitor combination, affinity of inhibitor or substrate for the cholinesterase, or protective effect of substrate upon the enzyme. However, the mutant consistently formed cholinesterase at about twice the wild-type rate. Mutation, in this case, appears to result in a specific change in the differential rate of enzyme biosynthesis. The relationship of this change to neostigmine resistance is discussed, and it is suggested that the effect observed here may be prototypic of a general type of mechanism responsible for acquired drug resistance.
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PMID:Mutation to neostigmine resistance in a cholinesterase-containing Pseudomonas. 1391 Feb 13

Incubation of neostigmine with normal human plasma in vitro results in the formation of two quaternary nitrogen compounds, one of which has been identified as m-hydroxyphenyltrimethylammonium. This hydrolysis is prevented by prior addition of dyflos to plasma in concentrations sufficient to inhibit plasma cholinesterase activity. The significance of these findings is discussed in relation to the occurrence of the same metabolic products in the urine of patients with myasthenia gravis treated with oral neostigmine. No equivalent findings are available for normal subjects since it was not considered justifiable to treat them with neostigmine.
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PMID:Hydrolysis of neostigmine by plasma cholinesterase. 1393 68

Organic ammonium salts of N-(2-benzoyloxyethyl)-alkyldimethylammonium bromide (BCHn-1) type are formed by the homological series Ar-COO(CH2)2-N+(CH3)2CnH2a + 1.Br-, whose structure contains a biodegradably labile ester bond, on the basis of which they rank among disinfectants and antiseptics of soft character. They are preferentially biotransformed hydrolytically to produce benzoic acid and substituted choline. The rapidity of enzymatic hydrolysis depends on the chemical structure (the length of the aliphatic chain on the ammonium nitrogen), it increases up to the number of 10 nitrogens of the aliphatic chain, and it rapidly decreases with further prolongation. The paper aimed to demonstrate the catalytic activity of butyrylcholinesterase on the enzymatic hydrolysis of selected organic ammonium salts in the medium of the microsomal fraction of the rat liver on the basis of inhibitory kinetic studies with physostigmine, a cholinesterase inhibitor. The product of enzymatic hydrolysis of BCHn-1, benzoic acid, was determined after extraction with chloroform from the acid medium by means of HPLC analysis with the use of the internal standard p-iodobenzoic acid at the wavelength of 228 nm. Kinetic parameters K(M) and VMAX were evaluated following Lineweaver-Burke using the method of linear regression analysis. The specific activity of butyrylcholinesterase (E.C.3.1.1.8) in the enzymatic hydrolytic process of BCHn-1 was significantly influenced by the presence of physostigmine, which was manifested by increased K(M), KI, and IC50 values in the investigated enzymatic process of selected substrates of the homological series BCHn-1, and by decreased VMAX and rate constants.
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PMID:[Catalytic activity of butyrylcholinesterase in biodegradation of organic ammonium salts in vitro]. 1509 77

A simple and sensitive reversed-phase liquid chromatography coupled with electrospray-mass spectrometry was developed and validated for the simultaneous determination of rivastigmine, a cholinesterase inhibitor, and its major metabolite NAP 226-90 in rat plasma and brain homogenates. Rivastigmine and NAP 226-90 were extracted from plasma and brain by ethyl acetate and, after drying under nitrogen, re-dissolved in acetonitrile and separated isocratic by HPLC on a C(18) column and quantified by single ion monitoring mass spectrometer. The mean (+/-SD) extraction efficiency for rivastigmine in plasma and brain was 93 +/- 2 and 95 +/- 2% (n = 5) of NAP 226-90 in a drug range of 10-100 pmol/mL or pmol/g. The method proved to be linear within the tested range (regression coefficient, r = 0.9999, n = 5). Intra- and inter-day precision coefficients of variation and accuracy bias were acceptable (within 15%, n = 5) over the entire range for both compounds using plasma or brain samples. The limits of quantification were 0.5 pmol/mL plasma and 2.5 pmol/g brain for rivastigmine and 1 pmol/mL plasma and 5 pmol/g brain for NAP 226-90, respectively. The analytical technique was used to determine the concentrations of rivastigmine and its metabolite NAP 226-90 in rat plasma and brain after oral drug administration. The concentrations of the parent drug and its major metabolite were compared to a pharmacodynamic parameter, the ex vivo inhibition of acetylcholinesterase.
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PMID:A simple, rapid and sensitive method for simultaneous determination of rivastigmine and its major metabolite NAP 226-90 in rat brain and plasma by reversed-phase liquid chromatography coupled to electrospray ionization mass spectrometry. 1510 1


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