KO CHjCHJK tCHjij

Inhibitors of acetylcholinesterase fall into two groups: the reversible carbamate inhibitors such as eserine (physostigmine (8.96)), neostigmine (8.97) and benzylpyrinium (8.98) and the irreversible organophosphorous inhibitors, dyflos

(8.99) and ecothiopate (8.100). The carbamates carry a positive charge and are bound at the anionic site (carboxylate ion) of the enzyme and correctly positioned to form a carbamyl enzyme with the serine hydroxyl group at the esteratic site (see Equation [8.36]). The carbamyl enzyme is only slowly decomposed (t1/2=~20 min) and in the presence of excess inhibitor the enzyme is partially locked up in this form so that its activity towards the substrate acetylcholine is decreased. Dilution or removal of excess inhibitor leads to a shift in the steady-state inhibition level with an increase in activity of the enzyme.

(07); neostigmine

The organophosphorus compounds rapidly react with the enzyme to form a stable phosphoryl enzyme and the enzyme is irreversibly inhibited (see Equation [8.37]).

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