STUDIES ON THE INTER-RELATIONSHIPS OF CERTAIN CHOLINERGIC COMPOUNDS

III. The Reactions Between 3-Acetoxy Phenyltrimethylammonium Methylsulfate, 3-Hydroxy Phenyltrimethylammonium Bromide and Cholinesterases

¹ Department of Pharmacology, Cornell University Medical Cottege, New York 21 , New York

The compound, 3-acetoxy phenyltrimethylammonium methylsulfate(Nu 2017) is relatively unstable in alkaline solution; it is somewhat more stable in neutral solution.

The hydrolysis of Nu 2017 is catalyzed by the cholinesterases of serum, erythrocytes and brain. The substrate concentration-reaction velocity curves in all of of these systems follow the Michaelis-Menten formulation. The hydrolysis of the compound is catalyzed more readily by serum cholinesterases than is the case with acetylcholine, but with erythrocyte and brain cholinesterases the converse is true. This lesser reactivity with specific cholinesterases may account for the more enduring action of Nu 2017 compared to acetylcholine in vivo.

Nu 2017 and its hydrolysis product, 3-hydroxy phenyltrimethylammonium ion (Nu 2561) inhibit erythrocyte cholinesterases to the same degree in equimolar concentrations.

Since Nu 2561 inhibits serum cholinesterases competitively, the inference is drawn from the erythrocyte data that Nu 2017 is a competitive inhibitor of cholinesterases.

The prior administration of a non-lethal dose of Nu 2017 prolongs the survival time of cats given a lethal dose of DFP.

It is pointed out that the complexity of the action of the choline esters and related compounds is such that their direct effects in vivo are always associated with a demonstrable inhibition of cholinesterase in vitro. It is presumed that the competitive inhibition that is demonstrable in vitro also occurs in vivo, but it is concluded that the direct effect of these agents is primarily responsible for their pharmacologic actions.