Abstract

Benzilylcholine mustard (N-2-chloroethyl-N-methyl 2-aminoethyl benzilate), a 2-haloalkylamine which cyclizes in solution to form an ethyleniminium derivative structurally very similar to benzilylcholine, was found to be a potent antagonist of the muscarinic action of acetylcholine. It differed from benzilylcholine in showing a much greater persistence of action, which was attributed to the alkylating activity of the ethyleniminium ion. Its action was highly specific, antagonism of the action of histamine and noradrenaline on smooth muscle requiring about 1000 times the concentration needed to block acetylcholine. It did not block ganglionic or neuromuscular transmission, but inhibited parasympathetic effects as well as the muscarinic actions of exogenous acetylcholine.

Blocking activity was confined to the ethyleniminium ion: neither the 2-chloroethyl-amine nor the alcoholic hydrolysis product was active.

In a study of the rate constants relating to the interaction of benzilylcholine and benzilylcholine mustard with acetylcholine receptors in guinea pig intestinal muscle, it was found that the association rate constant was similar for the two compounds, but that dissociation following alkylation by benzilylcholine mustard occurred at only [unknown] of the rate at which benzilylcholine dissociates. The complex initially formed by benzilylcholine mustard was a reversible one, but alkylation occurred rapidly, the rate of alkylation being considerably greater than that of dissociation of the reversible complex.