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)

Aldicarb toxicosis was diagnosed in 200 sheep that died suddenly. Carbamate insecticide toxicosis was suspected based on observed clinical signs (hypersalivation, diarrhea, urination, paddling, seizures, miosis, and deaths occurring within 1 hour). Tissue samples were submitted from 4 Columbian ewes for pathologic and analytical evaluation. Severe diffuse pulmonary edema was observed on gross and histologic examination. Inhibition of cholinesterase activity in retina (21.2-68.1% of normal activity, n = 3), brain (40.6-45.6% of normal activity, n = 3), and whole blood (27% of normal activity, n = 1) supported a diagnosis of carbamate toxicosis. Reversal of brain and whole blood cholinesterase activities (reactivation factor greater than 1.4) following an in vitro 1 hour incubation at 37 C was also consistent with carbamate poisoning. Aldicarb toxicosis was confirmed following its detection in rumen contents at 1.5, 5.5, and 334 ppm using both high-pressure liquid chromatography with UV detection and gas chromatography with nitrogen/phosphorus detection.
 ...
PMID:Aldicarb toxicosis in a flock of sheep. 155 68

Various carbamic acid esters (CAE) of a new class of dopaminergic drugs, 5-substituted 8-chloro-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1 H-3-benzazepines, were synthesized and evaluated as prodrug forms with the aim of protecting the parent phenols against first-pass metabolism following oral administration. Monosubstituted CAE were found to be highly unstable at pH 7.4 and 37 degrees C, the half-lives of hydrolysis being between 4 and 40 min. Plasma from various species catalyzed the hydrolysis of the carbamates. N,N-Disubstituted carbamates, on the other hand, were stable both in buffer and plasma solutions. They showed a very potent inhibition of butyrylcholinesterase (EC 3.1.1.8), but were less potent inhibitors of the specific erythrocyte acetylcholinesterase (EC 3.1.1.17). In vitro incubations of an N,N-dimethylsubstituted carbamate ester (10) with liver microsomes from mouse and rat showed an appreciable formation of the parent phenolic compound. This bioconversion is suggested to occur via an initial cytochrome P-450-catalyzed hydroxylation to give an N-hydroxymethyl derivative which spontaneously decomposes to the N-monomethylcarbamate. It is concluded that N,N-disubstituted carbamate esters may be potentially useful prodrugs for the 7-hydroxy-3-benzazepines, whereas N-monosubstituted carbamates appear to be too chemically and enzymatically labile.
 ...
PMID:Carbamate ester prodrugs of dopaminergic compounds: synthesis, stability, and bioconversion. 168 64

The carbamates, stabilized derivatives of carbamic acid, are potent biological agents used extensively in applications ranging from agriculture to medicine and industry. This review covers the two major classes of pesticidal carbamates: (1) cholinesterase-inhibiting carbamates which include monomethyl- and dimethylcarbamates (used primarily as insecticides); and (2) non-cholinesterase inhibiting, sulfur containing carbamates, the dithiocarbamates (used primarily as fungicides and herbicides). The dithiocarbamates include four major classes; (a) methyldithiocarbamates, (b) dimethyldithiocarbamates, (c) diethyldithio carbamates, (d) ethylenebisdithiocarbamates. For the purposes of this review neurotoxicity is defined as any unwanted change in the functional status of the organism which can be characterized in terms of behavioral, neurochemical, electrophysiological, or neuropathological indices. Neurotoxicity associated with methyl- and dimethylcarbamates has been characterized in terms of their reversible cholinesterase-inhibiting properties. The dithiocarbamates can have neurotoxic effects. However, a complete characterization of the neurotoxicity of these compounds has not been attempted. The neurotoxic actions of the dithiocarbamates may be related to their metal-chelating and enzyme-inhibiting properties.
 ...
PMID:Neurotoxicity of the pesticidal carbamates. 676 54

Carbamate compounds marked for their cholinesterase (ChE) inhibition are widely used as therapeutics and as insecticides. Groups of closely related carbamate molecules provide an important tool in the understanding of the domains responsible for binding these ligands to ChEs. Comparative inhibition profiles were derived for five N-methyl carbamates, mostly carbofuran derivatives, differing in length and branching of their hydrocarbonic chain towards human erythrocyte acetylcholinesterase (H.AChE), human serum butyrylcholinesterase (H.BChE) in its normal form or in a mutant form containing the point mutation Asp70-->Gly, and Drosophila nervous system ChE. Carbofuran was more toxic to all three ChEs than any of the other derivatives, with IC50 values which differed by more than 1000-fold. Drosophila ChE appeared to be most sensitive to all of the examined carbamates, and H.AChE was consistently more sensitive than H.BChE. Moreover, inhibition efficiency for H.BChE decreased more effectively than it did for H.AChE with increased length and complexity of the side chain, indicating less flexible carbamate binding site in BChE as compared with AChE. The Asp70-->Gly mutation had no apparent effect on H.BChE inhibition by N-methyl carbamates, suggesting that the Asp70 domain localized near the rim of the active site groove is not important in carbamate binding. Comparison of the carbamate IC50 values with published LD50 values demonstrated correlation between the in vivo toxicity and inhibition of BChE by carbamates, suggesting a biological in addition to scavenging importance for BChE in mammals. Pinpointing different domains characteristic of carbamate binding in each member of the ChE family can thus shed light on the variable toxicity of these inhibitors to insects and mammals, predict the toxicity of yet untested inhibitor molecules and help in designing novel and improved ChE inhibitors.
 ...
PMID:Molecular dissection of cholinesterase domains responsible for carbamate toxicity. 834 77

Organophosphate toxicity can be fatal. It accounts for almost 40 percent of all insecticide- and pesticide-related illnesses reported by the American Association of Poison Control Centers. Skin contamination is the most important route of occupational exposure. Carbamate insecticides exhibit a similar mechanism of acute toxicity. Organophosphate pesticides act as irreversible acetylcholinesterase inhibitors, while carbamate pesticides produce reversible effects. The inhibition of acetylcholinesterase causes accumulation of acetylcholine at nerve endings, resulting in a cholinergic or hypersecretory syndrome. Persons who are exposed to organophosphates must be admitted to the hospital for careful observation. Symptoms should be treated with atropine, and most patients should also receive pralidoxime, a cholinesterase-regenerating drug.
 ...
PMID:Cholinesterase-inhibiting insecticide toxicity. 850 47

Rasagiline (N-propargyl-1-(R)-aminoindan) is a selective, irreversible monoamine oxidase B (MAO B) inhibitor which has been developed as an anti-Parkinson drug. In controlled monotherapy and as adjunct to L-dopa it has shown anti-Parkinson activity. In cell culture (PC-12 and neuroblastoma SH-SY5Y cells) it exhibits neuroprotective and anti-apoptotic activity against several neurotoxins (SIN-1, MPTP, 6-hydroxydopamine and N-methyl-(R)-salsolinol) and ischemia. In vivo, it reduces the sequelae of traumatic brain injury in mice and speeds their recovery. The neuroprotective activity of rasagaline does not result from MAO B inhibition, since its S-enantiomer, TVP1022, which has 1000-fold weaker MAO inhibitory activity, exhibits similar neuroprotective properties. Introduction of a carbamate moiety into the rasagiline molecule to confer cholinesterase inhibitory activity for the treatment of Alzheimer's disease, resulted in compounds TV3326 [(N-Propargyl-(3R)Aminoindan-5-YL)-Ethyl Methyl Carbamate] and its S-enantiomer TV3279 [(N-Propargyl-(3S)Aminoindan-5-YL)-Ethyl Methyl Carbamate], which retain the neuroprotective activities of rasagiline and TVP1022. They also antagonize scopolamine-induced impairments in spatial memory. In addition, TV3326 exhibits brain-selective MAO A and B inhibitory activity after chronic administration and has antidepressant-like activity in the forced swim test. This is associated with an increase in brain levels of serotonin. The anti-apoptotic activity of these propargylamine-containing derivatives may be related to their ability to delay the opening of voltage-dependent anion channels (VDAC), which are part of the mitochondrial permeability transition pore. The propargylamine moiety is responsible for the increase in the mitochondrial family of Bcl-2 proteins, prevention in the fall in mitochondrial membrane potential, prevention of the activation of caspase 3, and of translocation of glyceraldehyde-3-phosphate dehydrogenase from the cytoplasm to the nucleus. The latter processes are closely associated with neurotoxin-induced apoptosis. Rasagiline interacts with and prevents the binding of PKI 1195 to the pro-apoptotic peripheral benzodiazepine receptor, which together with Bcl-2, hexokinase, porin, and adenine nucleotide translocator constitutes part of the VDAC. Furthermore, rasagiline, TV3326 and TV3279 are able to influence the processing of amyloid precursor protein by activation of alpha-secretase and increasing the release of soluble alpha APP in rat PC-12 and human neuroblastoma SH-SY5Y cells and in rat and mice cortex and hippocampus. This process has been shown to involve the upregulation of PKC and MAP kinase. It is quite likely that the induction of Bcl-2 and activation of PKC by rasagiline and TV3326 is closely linked to the anti-apoptotic action of these drugs and their ability to process APP by activation of alpha-secretase.
 ...
PMID:Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. 1204 33

Records of eagles, coyotes (Canis latrans), and red foxes (Vulpes vulpes) necropsied at the Western College of Veterinary Medicine, Saskatoon, Saskatchewan, Canada, between 1967 and 2002 were reviewed for cases suggestive of anticholinesterase poisoning. From 1993 to 2002, 54 putative poisoning incidents involving 70 bald eagles (Haliaeetus leucocephalus) and 10 golden eagles (Aquila chrysaetus) were identified. Of these, 50 incidents occurred in Saskatchewan, two were in Manitoba, and one occurred in each of Alberta and the Northwest Territories. The diagnosis was confirmed in eight instances by demonstration of pesticide in ingesta from eagles or known use of pesticide at the site together with brain cholinesterase (AChE) reduction of >50% in at least one animal. A presnmptive diagnosis of poisoning was made in 33 incidents based on brain AChE reduction of >50% in at least one animal; 13 incidents were considered suspicious because of circumstantial evidence of the death of eagles in association with other species and limited AChE reduction. Other wild species were found dead in 85% of the incidents involving eagles. Coyotes, foxes, black-billed magpies (Pica pica), and striped skunks (Mephitis mephitis) were associated with 34, six, six, and three incidents, respectively. There were eight additional incidents that did not involve eagles in which poisoning was diagnosed in coyotes. Carbofuran was identified in nine incidents. Carbamate poisoning was indicated on the basis of reactivation of brain AChE activity in two additional incidents. Brain AChE activity was not reduced from normal in eagles in four of seven incidents in which carbofuran was identified. The organophosplorous insecticide terbufos was found together with carbofuran in one incident. Brain AChE activity was measured in wild canids and in eagles in 15 incidents; in all of these incidents, brain AChE was redulced by >50% in at least one mammal, whereas this level of reduction occrred in eagles in only four incidents. Use of anticholinesterase pesticides to poison coyotes is illegal, but the practice continues and secondary poisoning of eagles is a problem of unknown proportions in western North America.
 ...
PMID:Secondary poisoning of eagles following intentional poisoning of coyotes with anticholinesterase pesticides in western Canada. 1536 15

Carbamate pesticides generally possess low toxicity for warm-blooded vertebrates, but developmental data are scarce. We have therefore evaluated embryotoxicity of choline esterase inhibitor bendiocarbamate in the chick embryo. The pesticide was dissolved in 5% acetone in distilled water and a volume of 200 microl was administered over the embryo through membrana papyracea on embryonic days 2, 3, 4, 5, and 10. Sampling was performed on embryonic day 10, while the embryos treated on embryonic day 10 were sampled on embryonic day 17. The toxicity of bendiocarbamate was fairly low, and LD50 decreased with advancing development from 1 mg/ embryo on embryonic day 2 to 29 mg on embryonic day 5. Malformations in surviving embryos were observed rarely (< 3 %) and occurred in both control and experimental groups. There was a mild but statistically significant dose-dependent reduction in body weight, most pronounced in the treatment on embryonic days 5 and 10, but the maximum difference from controls was below 15 %. A small but not significant increase in the number of positive cells was observed in the eye, limb buds, and the central nervous system of embryos treated on embryonic days 3 and 4 and examined after supravital whole-mount staining with Lysotracker Red for apoptosis. In agreement with previously published studies in other vertebrate animals, we conclude that bendiocarbamate does not possess significant toxicity in the avian embryo.
 ...
PMID:Bendiocarbamate toxicity in the chick embryo. 1945 80

Reversible inhibitors (e.g., pyridostigmine bromide, neostigmine bromide) of carbamate origin are used in the early treatment of Myasthenia gravis (MG) to block acetylcholinesterase (AChE) native function and conserve efficient amount of acetylcholine for decreasing number of nicotinic receptors. Carbamate inhibitors are known for many undesirable side effects related to the reversible inhibition of AChE. In contrast, this paper describes 20 newly prepared bispyridinium inhibitors of potential concern for MG. Although some compounds from this series have been known before, they were not assayed for cholinesterase inhibition yet. The newly prepared compounds were evaluated in vitro on human erythrocyte AChE and human plasmatic butyrylcholinesterase (BChE). Their inhibitory ability was expressed as IC(50) and compared to standard carbamate drugs. Three compounds presented promising inhibition (in muM range) of both enzymes in vitro similar to the used standards. The novel inhibitors did not present selectivity between AChE and BChE. Two newly prepared compounds were chosen for docking studies and confirmed apparent pi-pi or pi-cationic interactions aside enzyme's catalytic sites. The kinetics assay confirmed non-competitive inhibition of AChE by two best newly prepared compounds.
 ...
PMID:Preparation and in vitro screening of symmetrical bispyridinium cholinesterase inhibitors bearing different connecting linkage-initial study for Myasthenia gravis implications. 2013 18

Myasthenia gravis is a rare autoimmune neuromuscular junction disorder mainly caused by antibodies being targeted against the muscle acetylcholine receptors (AChRs). The loss of AChRs leads to a defect in neuromuscular transmission resulting in muscle weakness and fatigue. Although once an often fatal illness, Myasthenia gravis can now be well managed with relatively safe and effective treatments. However, the severe myasthenic cases associated with thymus tumors remain often fatal exception in the management of the disease. The early treatment includes the use of acetylcholinesterase inhibitors (AChEI) which enhance neuromuscular transmission. To ensure a peripheral effect, charged molecules are used, particularly quaternary ammonium salts. The structure of AChEIs has been continuously modified to obtain the optimal ratio between AChE inhibition and potential side-effects. This review summarizes progress in the use of quaternary compounds as AChE inhibitors in vitro with respect to their structure and inhibitory ability. Namely, carbamic acid esters, piperidinium and pyridinium salts, bisquaternary pyridinium salts and heterogeneous quaternary inhibitors are all discussed. Among data found in the literature, many compounds have shown promising inhibition of AChE when compared to commercial standards (pyridostigmine, neostigmine). Besides a promising inhibitory ability, selectivity for AChE versus butyrylcholinesterase (BChE) for the most potent compounds (sub-nanomolar IC(50)) was also identified.
 ...
PMID:Structure-activity relationship of quaternary acetylcholinesterase inhibitors - outlook for early myasthenia gravis treatment. 2034 42


1 2 Next >>