Organophosphate inhibitors

Application of the CCM to small sets (n < 6) of enzyme inhibitors revealed correlations between the inhibitory activity and the chirality measure of the inhibitors, calculated by Eq. (26) for the entire structure or for the substructure that interacts with the enzyme (pharmacophore) [41], This was done for arylammonium inhibitors of trypsin, Di-dopamine receptor inhibitors, and organophosphate inhibitors of trypsin, acetylcholine esterase, and butyrylcholine esterase. Because the CCM values are equal for opposite enantiomers, the method had to be applied separately to the two families of enantiomers (R- and S-enantiomers). 

A. M. Shafferman, C. Kronman, Y. Flashner, S. Leitner, H. Grosfeld, A. Ordenthch, Y. Gozes, S. Cohen, N. Ariel, D. Barak, M. Harel, I. Silman, J. L. Sussman, B. Velan, Mutagenesis of Human Acetylcholinesterase , J. Biol. Chem. 1992, 267, 17640-17648 A. Ordenthch, D. Barak, C. Kronman, N. Ariel, Y. Segall, B. Velan, A. M. Shafferman, The Architecture of Human Acetylchohnesterase Active Center Probed by Interactions with Selected Organophosphate Inhibitors , J. Biol. Chem. 1995, 271, 11953-11962. 

The organophosphate inhibitors are sometimes referred to as "irreversible" cholinesterase inhibitors, and edrophonium and the carbamates are considered "reversible" inhibitors because of the marked differences in duration of action. However, the molecular mechanisms of action of the three groups do not support this simplistic description. 

A third approach to protection against excessive acetylcholinesterase inhibition is pretreatment with reversible enzyme inhibitors to prevent binding of the irreversible organophosphate inhibitor. This prophylaxis can be achieved with pyridostigmine but is reserved for situations in which possibly lethal poisoning is anticipated, eg, chemical warfare (see Chapter 7). Simultaneous use of atropine is required to control muscarinic excess. 

Organophosphate inhibitors include aminotrimethylenephosphonate (AMP), hydroxyethylidene disphosphonate (HEDP), carboxylates and phosphate esters. They are often used in conjunction with other inhibitors such as zinc. Phosphorates generate protective films are susceptible to rupture, however, and pretreatment of the surfaces is often necessary. Organophosphate inhibitors work best in elevated pH environments, which reduces the corrosivity of the cooling wastes. 

Figure 9.17. Organophosphate inhibitors of acetylcholinesterase. a The catalytic mechanism, shown here for diiso-propylfluorophosphate(DFP).b Stmcturesof soman and tabun. Like DFP, these were developed during world war II as nerve gases , c Stractures of the insecticides parathion and malathion, and of paraoxon, which is the achve metabolite of parathion. (Malathion likewise requires conversion to malaoxon.) The arrow above the malathione stmcture indicates the esterase cleavage sites in its leaving group esterase cleavage occurs in human plasma and renders the molecule non-toxic.

The generality of this new type of shape-activity correlation is demonstrated for five receptor/substrate systems trypsin/arylammonium inhibitors the D2-dop-amine receptor/dopamine derivative agonists trypsin/organophosphate inhibitors acetylcholinesterase/organophosphates and butyrylcholinesterase/organo-phosphates. The correlations were obtained both for active-site induced chiral conformers and for inherently chiral inhibitors. Interestingly, for some of these cases the correlation of activity with structure is hidden when classical parameters, such as chain length, are taken, but is revealed with this shape descriptor. 

A., The architecture of human acetylcholinesterase active center probed by interactions with selected organophosphate inhibitors, J. Biol. Chem., 271,11953, 1996. 

Topical miotic agents are historically important glaucoma medications but are less commonly used today. Miotics lower lOP by causing muscarinic-induced contraction of the ciliary muscle, which facilitates aqueous outflow. They do not affect aqueous production. Multiple miotic agents have been developed. Pilocarpine and carbachol are cholinomimetics that stimulate muscarinic receptors. Ecbotbiopbate (Phospholine iodide) is an organophosphate inhibitor of acetylcholinesterase it is relatively stable in aqueous solution and, by virtue of its quaternary ammonium structure, is positively charged and poorly absorbed. The usefulness of these medicines is lessened by their numerous side effects and the need to use them three to four times a day. 

B. Mechanism of Action Both carbamate and organophosphate inhibitors bind to cholinesterase and undergo prompt hydrolysis. The alcohol portion of the molecule is then released. The acidic portion (carbamate ion or phosphate ion) is released much more slowly, thus preventing the binding and hydrolysis of acetylcholine. 

Too easy Highly potent organophosphate inhibitors of aeetyleholinesterase (eg, sarin, tabun) have been developed for chemieal warfare purposes. Their storage represents a potential toxi-... 

Cholinomimetic dmgs (carbamate, organophosphate inhibitors of acetylcholinesterase) Anxiety, agitation, seizures, coma, bradycardia or tachycardia, pinpoint pupils, salivation, sweating, hyperactive bowel, muscle fasciculations, then paralysis Support respiration. Treat with atropine and pralidoxime. Decontaminate... 

To date, anatoxin-a(S) is the only known natural organophosphate inhibitor of the neuronal enzyme acetylcholinesterase. The freshwater environment... 

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