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FIGURE 8-1 Steps in the hydrolysis of acetylcholine by acetylcholinesterase and in the inhibition and reactivation of AChE. Only the three residues of the catalytic triad are depicted. The associations and reactions shown are: A. Acetylcholine (ACh) catalysis: binding of ACh, formation of a tetrahedral transition state, formation of the acetyl enzyme with liberation of choline, rapid hydrolysis of the acetyl enzyme with return to the original state. B. Reversible binding and inhibition by edrophonium. C. Neostigmine reaction with and inhibition of acetylcholinesterase (AChE): reversible binding of neostigmine, formation of the dimethyl carbamoyl enzyme, slow hydrolysis of the dimethyl carbamoyl enzyme. D. Diisopropyl fluorophosphate (DFP) reaction and inhibition of AChE: reversible binding of DFP, formation of the diisopropyl phosphoryl enzyme, formation of the aged monoisopropyl phosphoryl enzyme. Hydrolysis of the diisopropyl enzyme is very slow and is not shown. The aged monoisopropyl phosphoryl enzyme is virtually resistant to hydrolysis and reactivation. The tetrahedral transition state of ACh hydrolysis resembles the conjugates formed by the tetrahedral phosphate inhibitors and accounts for their potency. Amide bond hydrogens from Gly 121 and 122 stabilize the carbonyl and phorphoryl oxygens. E. Reactivation of the diisopropyl phosphoryl enzyme by pralidoxime (2-PAM). 2-PAM attack of the phosphorus on the phosphorylated enzyme will form a phospho-oxime with regeneration of active enzyme.

FIGURE 8-1 Steps in the hydrolysis of acetylcholine by acetylcholinesterase and in the inhibition and reactivation of AChE. Only the three residues of the catalytic triad are depicted. The associations and reactions shown are: A. Acetylcholine (ACh) catalysis: binding of ACh, formation of a tetrahedral transition state, formation of the acetyl enzyme with liberation of choline, rapid hydrolysis of the acetyl enzyme with return to the original state. B. Reversible binding and inhibition by edrophonium. C. Neostigmine reaction with and inhibition of acetylcholinesterase (AChE): reversible binding of neostigmine, formation of the dimethyl carbamoyl enzyme, slow hydrolysis of the dimethyl carbamoyl enzyme. D. Diisopropyl fluorophosphate (DFP) reaction and inhibition of AChE: reversible binding of DFP, formation of the diisopropyl phosphoryl enzyme, formation of the aged monoisopropyl phosphoryl enzyme. Hydrolysis of the diisopropyl enzyme is very slow and is not shown. The aged monoisopropyl phosphoryl enzyme is virtually resistant to hydrolysis and reactivation. The tetrahedral transition state of ACh hydrolysis resembles the conjugates formed by the tetrahedral phosphate inhibitors and accounts for their potency. Amide bond hydrogens from Gly 121 and 122 stabilize the carbonyl and phorphoryl oxygens. E. Reactivation of the diisopropyl phosphoryl enzyme by pralidoxime (2-PAM). 2-PAM attack of the phosphorus on the phosphorylated enzyme will form a phospho-oxime with regeneration of active enzyme.

"Reversible" Carbamate Inhibitors

Therapeutically useful drugs of this class of interest are shown in Figure 8—2; the essential moiety of physostigmine is a methylcarbamate of an amine-substituted phenol. An increase in anti-ChE potency and duration of action results from the linking of two quaternary ammonium moieties. One such example is the miotic agent demecarium (2 neostigmine molecules connected by a series of 10 methylene groups). The second quaternary group confers additional stability to the drug-AChE interaction. Carbamoylating inhibitors with high lipid solubilities (e.g., rivastigmine), which readily cross the blood—brain barrier and have longer durations of action, are approved or in clinical trial for the treatment of Alzheimer's disease (see Chapter 20).

The carbamate insecticides carbaryl (sevin), propoxur (baygon), and aldicarb (temik), which are used extensively as garden insecticides, inhibit ChE in a fashion identical with other car-bamoylating inhibitors.

Organophosphorus Compounds

The prototypic compound is DFP, which produces virtually irreversible inactivation of AChE and other esterases by alkylphosphorylation. its high lipid solubility, low molecular weight, and volatility facilitate inhalation, transdermal absorption, and penetration into the CNs. After desul-furation, the insecticides in current use form the dimethoxy or diethoxyphosphoryl enzyme.

Malathion, parathion, and methylparathion have been popular insecticides. Acute and chronic toxicity has limited the use of parathion and methylparathion, and potentially less hazardous compounds have replaced them. The parent compounds are inactive in inhibiting AChE in vitro; they must be activated in vivo via a phosphoryl oxygen for sulfur substitution (phosphothioate to ch3 +

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