Interactions of quaternary ammonium drugs with acetylcholinesterase and acetylcholine receptor of Torpedo electric organ

The structure-activity relationship of 16 quaternary ammonium compounds was studied on the activity of acetylcholinesterase (ACh-esterase; EC 3.1.1.7), on the binding of ( super(3)H) acetylcholine (( super(3)H)ACh) and ( super(3)H) phencyclidine (( super(3)H)PCP) to the "receptor" and "channel" sites, respectively, of the nicotinic ACh receptor, and on the receptor-regulated super(22) Na influx into microsacs made from the electric organ membranes of the electric ray, Torpedo species. Methyl- beta -dimethylammonium propionate methiodide was the most potent inhibitor of binding to the receptor site and the least potent inhibitor of ACh-esterase activity, which was inhibited most effectively by hydroxyphenolic compounds. Introduction of an m-hydroxy group on the phenyltrimethylammonium had little effect on binding to the receptor site, but dramatically increased its anti-ACh-esterase potency. Increasing steric hindrance reduced the affinity of these drugs for the receptor sites, while attachment of an aromatic ring to the onium group dramatically increased it.