The Conversion of Methyl-2-Acetoxyethyl-2′-Chloroethylamine to an Acetylcholine-Like Aziridinium Ion and its Action on the Isolated Guinea Pig Ileum

Methyl-2-acetoxyethyl-2′-chloroethylamine (acetyicholine-mustard) isomerizes in aqueous solution to form a cyclic ion, N-methyl-N-(2-acetoxyethyl)aziridinium, which structurally resembles acetylcholine. It is a potent stimulant of the guinea pig ileum, being approximately one-sixth as potent as acetylcholine at pH 7.4 and one-third as potent at pH 8.4. The agonist activity is inhibited by atropine, by preincubation with acetylcholinesterase, and pretreatment with thiosulfate ion. Mepyramine does not inhibit the stimulant action.One hour exposures of ileum segments to concentrations of acetylcholine-mustard in excess of those producing maximal responses, followed by a 1 h recovery period, did not produce evidence of postsynaptic receptor alkylation. Post-treatment responses to acetylcholine were slightly depressed, but these reductions were not related to the incubation concentrations of the agonist haloalkylamine. Pilocarpine-induced responses were unaltered by this treatment whereas 5-hydroxytryptamine responses were slightly potentiated and histamine responses were slightly and inconsistently modified.These treatments produced persistent, dose-related increases in muscle tone, an effect consistent with accumulations of spontaneously liberated acetylcholine and possibly caused by inhibition of in situ acetylcholinesterase.Ostensibly, the evidence suggests that the acetylcholine-like aziridinium ion can stimulate, but not inhibit, the muscarinic receptors of the guinea pig ileum.