Anticholinesterase activity

The alkyl and alkoxy substituents of phosphate or phosphonate esters also affect the phosphorylating abiUty of the compound through steric and inductive effects. A satisfactory correlation has been developed between the quantitative measure of these effects, Tafts s O, and anticholinesterase activity as well as toxicity (33). Thus long-chain and highly branched alkyl and alkoxy groups attached to phosphoms promote high stabiUty and low biological activity. 

All these observations underscore the potential for application of appropriate OPAs to the destruction of organophosphorus compounds with anticholinesterase activity (Cheng and Calomiris 1996). However, since, hydrolysis results in release of fluoride, the possibility of its subsequent incorporation into organic substrates to produce fluoroacetate and 4-fluorothreonine (Reid et al. 1995) may be worth consideration. 

I. 1-cyclohexylpiperidine derivatives Anticholinesterase activity and antagonistic activity to acetylcholine. Biochem Pharmacol 23 1263-1281, 1974. 

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). 

Toxification rates may vary. For example, when humans are acutely poisoned by the systemic insecticide menazon, there is an incubation period (of up to one day) and a slow growth in the anticholinesterase activity when the PS-form with low toxicity becomes the active PO-form [A17]. 

Thirugnanam, M. and A.J. Forgash. 1977. Environmental impact of mosquito pesticides toxicity and anticholinesterase activity of chlorpyrifos to fish in a salt marsh habitat. Arch. Environ Contam, Toxicol. 5 415-425. Tsuda, T., S. Aoki, T. Inoue, and M. Kojima. 1994. Accumulation and excretion of pesticides used as insecticides or fungicides in agricultural products by the willow shiner Gnathopogon caerulescens. Comp. Biochem. Physiol. 107C 469-473. 

Reference has repeatedly been made to the powerful anticholinesterase activity of D.F.P. (p. 61). Towards pseudocholinesterase, for example, it is effective in concentration as low as 10 11M. In order to throw light on its mode of action with esterases,3 radioactive D.F.P. containing 32P was prepared.4 An account of its production on what may be conveniently called the one-gram scale , directly from phosphorus, is given below. 

This ester, isopropyl methylphosphonofluoridate (X), is a colourless liquid. It is more toxic than D.F.P., but shows very similar physiological properties, intense myosis, respiratory collapse, powerful anticholinesterase activity, etc. The liquid passes rapidly through the skin. At the end of World War II, two plants were under construction in Germany for the production of the material on a large scale. 

As stated previously (pp. 62 etseq.) there is often correlation between anticholinesterase activity in vitro and gross mammalian toxicity. The toxicity of O.M.P.A. is not very muoh less than that of tabun, D.F.P. and T.E.P.P., yet the anti-cholinesterase activity of O.M.P.A. in vitro is negligible (50 per cent inhibition, 4-5x10 2m). On the other hand, O.M.P.A. produces all the symptoms of acetylcholine poisoning when administered to animals. Moreover, the serum cholinesterase of such animals is almost completely inhibited. Another anomaly of O.M.P.A. is that toxic action is slower than that of D.F.P. or tabun, an hour s delay being usual compared to the very quick knock-out action of D.F.P., etc. (see p. 2). 

Hartley4 has shown that chemical oxidation of O.M.P.A. using potassium permanganate leads to the transfer of one oxygen atom per molecule of O.M.P.A. An alkali-labile substance of increased anticholinesterase activity was thereby produced. 

Besides compounds in which X = F, toxicity and anticholinesterase activity are observed in compounds in which X represents an anhydride , e.g. alkyl pyrophosphates (T.E.P.P.), p-nitrophenyl esters. 

Anticholinesterase activity has been reported for pyridaphenthion [Pyri-dafenthion, Ofunack CAS 119-12-0 (104)]. Some 4-styrylpyridazines (105) have been found to inhibit choline acetyltransferase in vitro [433]. 

OkeUo El, Savelev SU, Perry EK (2004) In vitro anti-beta-secretase and dual anticholinesterase activities of Camellia sinensis L. relevant to treatment of dementia. Phytother Res 18 624-627... 

Alcala MDM, Vivas NM, Hospital S, et ai. Characterisation of the anticholinesterase activity of two new tacrine-huperzine A hybrids, Neuropharmacol... 

Autmomic o-bungaro- polypqjtThigh anticholinesterase activity Formosan banded krait. 

Sqjcic, K. Guella, G. Mancini, I. Pi ra, F. Dalla Sara, M. Maiestrina, G. Tubbs, K. Macek, P. Turk, T. (1997) Characterization of anticholinesterase-active 3-all lpyridinium polymers frmn the marine sponge Reniera sarai in aqueous solution. J. Nat. Prod., 60, 991-6. 

DeJong, L.P.A., and Ceulen, D.l. Anticholinesterase activity and rate of decomposition of some phosphylated oximes. Biochem. Pharmacol. 27 857-863, 1978. 

Researchers (Benilova et al., 2006 Arkhypova et al., 2008) are developing a biosensor-based pH-sensitive field-effect transistor technology for rapid determination of glycoalkaloids. The test takes advantage of the anticholinesterase activity of the glycoalkaloids. These tests could hold great promise, analogous to the ELISA test mentioned above. 

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