Inhibitors of cholinesterase

The toxic organic phosphorus compounds act as powerful inhibitors of cholinesterase, an enzyme found predominantly in the nervous tissue of animals, including insects. This enzyme hydrolyzes acetylcholine, which plays an essential role in the transmission of nerve impulses. The toxicity of compounds in this series can be largely accounted for on the basis of their anticholinesterase activity (7,8,12,14, SI). 

T Anders, LA Svensson. Bambuterol, a carbamate ester prodrug of terbutaline, as inhibitor of cholinesterases in human blood. Drug Metabol Dispos 16(5) 759-763,... 

The activity of allelochemicals inhibitors of cholinesterase was assayed as listed below ... 

Krasowski MD, McGehee DS, Moss J. (1997). Natural inhibitors of cholinesterases implications for adverse drug reactions. Can J Anaesthesiol. 44(5) 525-34. 

Toxicology. Azinphos-methyl is an indirect inhibitor of cholinesterase. 

Gl disease/dysfunction Tacrine is an inhibitor of cholinesterase and may be expected to increase gastric acid secretion caused by increased cholinergic activity. Therefore, closely monitor patients at increased risk for developing ulcers for symptoms of active or occult Gl bleeding. 

Difluorophate (diisopropyl fluorophosphate) is an irreversible inhibitor of cholinesterase. It has been used in the treatment of glaucoma (Figure 8.87). 

Lamb, J.C., Steinberg, G.M., and Hackley, B.E., Jr. Isopropyl methylphosphonylated bisquatemary oximes powerful inhibitors of cholinesterase. Biochlm. Biophys. Acta 89 174-176, 1964. 

Castro found DM and CS to be active Inhibitors of cholinesterase and suggested that this characteristic might explain their lacrlmatory effect. Roberts et al. demonstrated a direct effect of DM on gastric activity and, like Striker et al., H 12 found solid evidence that its lethal effects are of respiratory origin. 

The reactivator may affect enzymes other than those Involved directly in the actions of the Inhibitor of cholinesterase. 

The reactivator may form, either with the inhibitor or with its residue in inhibited cholinesterase, a stable secondary inhibitor of cholinesterase. 

The last three mechanisms of action, and possibly the other two as well, are Involved in the causation of the side effects that have been reported to occur either in normal subjects to whom reactivators had been administered during research projects or in patients who had been given reactivators as therapy for intoxication by pesti-cldal anticholinesterases or other inhibitors of cholinesterases. 

The second-order rate constant for the reaction between sarin and either 2-PAM I or II was found to be 170 L/mol per minute. If a phosphorylated or phosphonylated oxime that does not enter rapidly into the second step above is formed, that product may be an Inhibitor of cholinesterase. 7,88 Hydrolysis of sarin in the presence of 200-fold concentrations of V and II took place more rapidly in plasma from rats with the former oxime than with the... 

Toxicity Bendiocarb is moderately toxic if it is ingested or absorbed through the skin. Skin absorption is the most likely route of exposure. It is a mild irritant to the skin and eyes.4 Like other carbamate insecticides, bendiocarb is a reversible inhibitor of cholinesterase, an essential nervous system enzyme. Symptoms of bendiocarb poisoning include weakness, blurred vision, headache, nausea, abdominal cramps, chest discomfort, constriction of pupils, sweating, muscle tremors, and decreased pulse. 

Based on the above discussion it was thought that the trifluoro-methyl ketones would be more polarized and thus create a great electrophilicity on the carbonyl carbon which facilitates -OH attack by the serine residue. Yet there is no carbon-oxygen bond to be cleaved In the ketone moiety, and therefore the enzyme-trifluoromethyl ketone transition state complex does not undergo catalytic conversion. The above rationale seems reasonable as trifluoromethyl ketones were found to be extraordinary selective and potent inhibitors of cholinesterases (56) of JHE from T. ni (57) and of meperidine carboxylesterases from mouse and human livers (58). Since JH homologs are alpha-beta unsaturated esters, a sulfide bond was placed beta to the carbonyl in hopes that it would mimic the 2,3-olefln of JHs and yield more powerful inhibitors (54). This empirical approach was extremely successful since it resulted in compounds that were extremely potent inhibitors of JHEs from different species (51,54,59). 

Dichlorvos is a known inhibitor of cholinesterase, and it is likely that under certain conditions of use, a significant degree of inhibition might occur. However, under the conditions of these experiments, no such effect appears to have occurred. The subjects indicated no adverse effects. 

The biological properties of pseudophrynamines have not been explored. The structures are reminiscent of physostigmine, which is a potent inhibitor of cholinesterases. 

Prozorovskii, V.B., Chepur, S.V. (2001). New data on non-synaptic (distant) effects of organophosphorus inhibitors of cholinesterase. Toksikologicheskii vestnik [Toxicological Bulletin] 4 2-7. (In Russian)... 

Kassa, J. (1998). Non-specific effects of organophosphorus inhibitors of cholinesterases. Voj. Zdrav. Listy 67 15-19. 

These compounds inhibit the hydrolysis of the neurotransmitter acetylcholine by the enzyme acetylcholinesterase within the mammalian nervous system (Zwiener and Ginsburg, 1988). This inhibition causes acetylcholine levels to rise, thus causing cholinergic hyperstimulation at muscarinic and nicotinic receptors. There are important differences in the way carbamates and OPs bind to acetylcholinesterase as well as their abililty to affect the CNS. Carbamates are reversible inhibitors of cholinesterase enzymes. Carbamates create a reversible bond to the cholinesterase enzyme through carbamylation which can spontaneously hydrolyze, reversing toxicity. Carbamate poisoning produces toxicity similar to that of OPs however, the toxicity is usually of a shorter duration and less severe in nature (Lifshitz et al, 1994). In contrast, OPs inhibit cholinesterase via an irreversible bond of phosphate radicals... 

Toxic action is complex, involving both stimulation and blockade of autonomic ganglia and skeletal muscle neuromuscular junctions, as well as direct effects on the central nervous system. Paralysis and vascular collapse are prominent features of acute poisoning, but death is usually due to respiratory paralysis, which may ensue promptly after the first symptoms of poisoning. Nicotine is not an inhibitor of cholinesterase enzyme. 

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