Organophosphorus inhibitors

Irreversible anticholinesterases include the organophosphorus inhibitors and ambenonium, which irreversibly phosphorylate the esteratic site. Such drugs have few clinical uses but have been developed as insecticides and nerve gases. Besides blocking the muscarinic receptors with atropine sulphate in an attempt to reduce the toxic effects that result from an accumulation of acetylcholine, the only specific treatment for organopho-sphate poisoning would appear to be the administration of 2-pyridine aldoxime methiodide, which increases the rate of dissociation of the organophosphate from the esteratic site on the enzyme surface. 

Selected entries from Methods in Enzymology [vol, page(s)] Types of organophosphorus inhibitors, 11,686-688 toxicity hazards, 11,688 purity and analysis, 11,688 solutions of organophosphorus compounds, 11,689 estimation of specific radioactivity of organophosphorus compounds, 11,689-690 method for estimating phosphorus content, 11,691 reactions with enzymes, 11,691 -701 [rate constants, 11,692 phosphorylation of chymotrypsin, 11, 694-696 identification of phosphoryl and phosphonyl peptides,... 

The phosphorylated esterases formed by the action of organophosphorus inhibitors are very stable, but some antidotes can reverse the inhibition. The oxime of 2-formyl-l-methylpyridinium ion (pralidoxime) is very effective.6 Its positive charge permits it to bind to the site normally occupied by the quartemary nitrogen of acetylcholine and to displace the dialkylphospho group ... 

Diisopropylfluorophosphate (DFP) and phenylmethanesulfonyl fluoride (PMSF), both organophosphorus inhibitors, are potent irreversible inhibitors of serine proteases. However, because of their additional inhibition of acetylcholinesterase these compounds are highly toxic [26]. Another toxic but potent trypsin inhibitor is (4-aminophenyl)-methanesulfonyl... 

Other anticholinesterases recently licensed in Europe include metrifonate. This is an irreversible organophosphorus inhibitor of acetylcholinesterase and is a pro-drug for dichlorvos. The development of metrifonate was delayed because some patients developed muscle weakness and a delayed neurotoxicity has been described for compounds that are chemically related to the drug. 

Representatives of this class of inhibitors are DFP (diisopropylfluoro-phosphate), PMSF (phenylmethylsulfonyl fluoride), APMSF (4-aminophe-nyl)-methanesulfonyl, AEBSF (4-(2-aminoethyl)-benzenesulfonyl fluoride), FK-448 (4-(4-isopropylpiperadinocarbonyl) phenyl 1,2,3,4,-tetrahydro-1-naphthoate methanesulfonate), camostat mesilate (7V,/V -dimethyl carba-moylmethyl-/)-(/> -guanidino-benzoyloxy)phenylacetate methanesulfonate), and Na-glycocholate. The organophosphorus inhibitors DFP and PMSF are potent irreversible inhibitors of serine proteases. Due to their... 

A. Ordentlich, D. Barak, C. Kronman, H.P. Benschop, L.P.A. De Jong, N. Ariel, R. Barak, Y. Segall, B. VelanandA. Shafferman, Exploring the active center of human acetylcholinesterase with stereomers of an organophosphorus inhibitor with two chiral centers, Biochemistry, 38, 3055-3066 (1991). 

J Grembecka, A Mucha, T Cierpicki, P Kafarski (2003) The most potent organophosphorus inhibitors of leucine aminopeptidase Structure-based design, chemistry, and activity, J Med Chem 46(13) 2641—2655... 

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. 

From a chemical point of view, AChE reactivators are mono- or bis-quatemary pyridinium salts bearing in their molecule a functional oxime group able to split the bond between the organophosphorus inhibitor and the enzyme, to release free functional enzymes to once again be physiologically active in the organism (Figure 66.4). 

Benomyl is a microtubule-disrupting agent in fungi. This agent may cause chromosomal aberrations (e.g., aneuploidy). There is very little evidence of benomyl toxicity in mammals, however. Benomyl itself does not have any direct effect on acetylcholinesterase. Under certain conditions, however, benomyl breaks down to produce carbendazim and butyl isocyanate, of which the isocyanate is an irreversible inhibitor of acetylcholinesterase with comparable potency to some active organophosphorus inhibitors. 

Fig. 9.8 Structure of organophosphorus inhibitors which are TAG analogues. From [92, 99].

Makhaeva G., and Malygin V., Different specificity of acethylcholinesterase and neuropathy target esterase to organophosphorus inhibitors. The 12th ESN Meeting, St.-Petersburg, Abstracts, J. Neurochem., 71 (Suppl.), S21, 1998. 

Misulis KE, Clinton ME, Dettbarn W-D et al. (1987). Differences in central and peripheral neural actions between soman and diisopropyl fluorophos-phate, organophosphorus inhibitors of acetylcholinesterases. Toxicol Appl Pharmacol, 89,391-398. 

Clouet, D.. and Waelsch, H. (1963). Amino acid and protein metabolism in the brain. The effect of an organophosphorus inhibitor on the incorporation of C-lysine into the proteins of rat brain. J. Neurockem. 10,51-6.3. 

Feriuga. J., Asherson, G. L and Becker. E, L. (1972). The effect of organophosphorus inhibitor.s, p-nitrophcnol and cyiocha-lasin B. on cytotoxic killing of tumour cells by immune spleen cells, and the effect of shaking, immunology 23,577-590. 

The organophosphorus inhibitors have very high affinity for the active site of acetylcholinesterase. Once bound, these agents inactivate the enzyme by phosphorylation. Regeneration of the enzyme is so slow that a single dose of DFP inhibits acetylcholinesterase for over a week. 

Karalliedde, L.D., Edwards, P, Marts, T.C., 2003. Variables influencing the toxic response to organophosphates in humans. Food Chem. Toxicol. 41, 1-13. Kassa, J., 1998. Non-specific effects of organophosphorus inhibitors of cholinesterases. Voj. Zdrav. Listy 67, 15-19. 

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