The Mechanism of Anticurare Action of Certain Neostigmine Analogues

Recently Randall and Lehmann (1950) and Randall (1950) reported on a number of neostigmine analogues which had a striking anticurare action in cats and dogs in vivo but were only weak cholinesterase inhibitors in vitro.Their findings were confirmed by McFarlane, Pelikan, and Unna (1950) and Artusio, Riker, and Wescoe (1950) in man, and by Riker and Wescoe (1950) and Wescoe, Riker, and Brothers (1949) in cats.The compounds these authors had studied were either hydroxy anilinium salts or esters of these salts (excluding the carbamic esters).It was found that these substances differed from neostigmine in that the peak of anticurare action was reached within a minute after the injection and that side effects, e.g.salivation and bradycardia, were either negligible or absent.A further advantage was that they could be given at relatively short intervals without loss of their anticurare potency or a decrease in the sensitivity of the endplate to d-tubocurarine.It is now generally held that tubocurarine blocks neuromuscular transmission by competing with acetylcholine for the receptors on which the latter acts.In this way it raises the threshold for stimulation.This blocking effect of tubocurarine can be overcome by anticholinesterases, dyes, potassium salts and phenols, or by sub- stances which stimulate the endplate, each type of compound exerting an anticurare action by a different mechanism.There was difficulty in attributing the action of the neostigmine analogues to any of the known anticurare mechanisms.Randall and Lehmann (1950) thought that the anticholinesterase activity-about 1/100th or less of that of neostigmine-was too small to account for the anticurare action, which was about one quarter that of neostigmine; these authors also excluded a stimulant action on the endplate, because, although some of the compounds caused a contrac- ture of the muscle in small concentrations, others had no stimulant properties what- soever.Riker et al. (1949), Wescoe et al. (1949), Artusio et al. (1950), and McFarlane et al. (1950), studying only compounds with good stimulating properties, took the view that the anticurare action could be entirely accounted for by a stimulant action on the endplate.Randall (1950) in continuation of his work came to similar con- clusions, but also considered the possibility that the free phenolic group, present in many of the compounds, might be of importance.In the experiments to be described I have studied four of the neostigmine analogues in normal and curarized cats, on the isolated phrenic nerve diaphragm of the rat, on the rat intestine, and on the frog rectus.