THE SELECTIVE ANTI-CHOLINERGIC ACTIVITY OF ALIPHATIC TRIS-QUATERNARY AMMONIUM COMPOUNDS

¹ Department of Pharmacology, Cornell University Medical College

A new series of aliphatic tris onium compounds in which the number of carbon atoms between the onium groups varied from five to nine has been examined for pharmacologic activity in the cat. In each case, the ethonium as well as the methonium compound has been examined.

Two types of activity have been detected, namely the production of a neuromuscular blockade and the inhibition of vagal slowing of the heart.

With respect to both types of activity the nonane derivatives showed the greatest activity and the lower homologs progressively less. In addition, the ethonium derivatives were more active than their methonium analogs.

The pentane and hexane, as well as the other derivatives, showed no appreciable ganglionic blocking activity.

The most active curariform compound among this series was found to be 5-(4-diethylaminobutyl)-1,9-bis-diethylamino nonane tri-ethobromide. In the rabbit head drop assay, it was found to be 40 per cent as active as gallamine. Its mode of neuromuscular blocking action is similar to that of gallamine and d-tubocurarine in that it is antagonized by edrophonium in the kitten diaphragm preparation and antagonizes the stimulatory activity of acetyicholine on the frog rectus abdominis muscle.

The ethonium nonane derivative was also the most potent compound in this series in blocking vagal slowing of the heart in the cat. On the basis of the respective doses required to produce a 50 per cent inhibition of vagal cardiac slowing under the conditions described, the nonane derivative was five times as active as gallamine. The mode of action of the ethonium nonane derivative on vagal inhibition of heart rate is similar to that of gallamine and atropine in that the slowing of cardiac rate produced by methacholine was inhibited. Like gallamine but unlike atropine the nonane derivative did not significantly alter the fall in blood pressure caused by methacholine, did not antagonize the action of acetylcholine on cat duodenal strips, and did not block salivary secretion caused by the intra-arterial injection of acetylcholine or chorda tympani nerve stimulation. Whether this derivative is active at any other atropine sensitive sites has not as yet been determined. The data do suggest, however, that it may be possible to develop polyonium anti-cholinergic compounds of markedly greater specificity of action than those in current use.