NERVE ACTIVITY 



briefly outlined as illustrating how the studies of the molecular 

 forces in the interaction between acetylcholinesterase and its 

 substrate have advanced and stimulated the understanding of the 

 pharmacology and physiology of the nerve cell. 



MECHANISM OF NERVE GAS ACTION 



Certain phosphate esters, such as tetraalkyl pyrophosphates, 

 dialkyl j&-nitrophenyl phosphates, and dialkyl fluorophosphates, 

 are potent irreversible inhibitors of acetylcholinesterase (and 

 esterases in general) . These compounds are of general interest 

 because the most potent chemical warfare gases and some power- 

 ful insecticides belong to this class and owe their lethal action to 

 their inactivation of cholinesterase (25). 



During the studies of the molecular forces of interaction 

 between acetylcholinesterase and its substrate and the hydrolytic 

 mechanism, the mechanism of nerve gas inhibition became evi- 

 dent (35,37,42). Inhibition by these substances is not removed 

 by dialysis nor by dilution, i.e., it is, according to the customary 

 criteria, irreversible. The structure of these compounds and the 

 fact that the highest inhibition is obtained at those />H's in which 

 the enzyme is most active, indicated that these compounds enter 

 the hydrolytic mechanism and phosphorylate the same basic 

 group in the esteratic site which — in the physiological process — 

 is acetylated. Thus 



O 



II G® 



H— G + (RO)2P— F > II 4- HF 



P— oe 



/\ 

 OR OR 



The dialkylphosphoryl enzyme, in contrast to the acetyl enzyme 

 does not readily react with water to regenerate the free and active 

 enzyme, and thus these substances are inhibitors rather than 

 substrates. The reaction with water is, however, rapid enough 

 to be readily demonstrated in a number of cases. Diethyl- 

 phosphoryl enzyme obtained either by tetraethylpyrophosphate 



639 



