Molecular Pharmacology, Vol 6, 41-45, Copyright © 1970 by the American Society for Pharmacology and Experimental Therapeutics

Kinetic Effects of Leptocurares and Pachycurares on the Methanesulfonylation of Acetylcholinesterase

A Correlation with Pharmacodynamic Properties

¹ Departments of Chemistry and Biochemistry, University of Ottawa, Ottawa 2, Ontario, Canada

It was shown previously that the alkyltrimethylammonium ion series of cholinergicl and anticholinergic drugs not only fail to protect acetylcholinesterase (AChE) against irreversible esterification by methanesulfonyl fluoride of its active serine hydroxyl, but actually accelerate the reaction, thus showing that the alkyl chains do not bind bind on the catalytic esteratic sites themselves (exo orientation). Acceleration has been explain in terms of conformational perturbations, and maximum potency in this regard was exhibited by the n-hexyl membber, followed by a sharp reversal of the acceleration trend at the n-heptyl member. Parallel trends and shifts in potencies at the receptor level are well documented. Using the same experimental techniques, it has now been found that leptocurares (polymethoniums of the decamethonium series, including succinylcholine) also behave as accelerators of the methanesulfonylation reaction, peak activity being observed with decamethonium. Succinylcholine was 4 times more active than the latter in stimulating the methanesulfonylation reaction. The trend in stimulating potencies closely parallels the relative blocking potencies at the motor end plate level. In marked contrast, d-tubocurarine and gallamine protect AChE against methanesulfonyl fluoride by a mechanism which does not obey the laws of competitive kinetics. The application of conventional assay techniques had previously led to the conclusion that pachycurares are competitive inhibitors of the cationic substrate ACh at both the enzyme and myoneural junction levels. However, evidence that the inhibition is rather of the partially competitive type has recently been reported. Since the methanesulfonyl fluoride molecule, unlike ACh, carries no charge, it can hardly compete directly with pachycurares for charged binding sites. Hence, the observed partially competitive relationship must be the result of pachycurare-induced change transmitted to the esteratic center from outer anionic sites. These contrasting properties of leptocurares and pachycurares as modifiers of conformation find an exact parallel in the divergence of their mechanisms of blockade at the myoneural junction level. These observations furnish new insight into the interaction topographies underlying the ligand-induced conformational changes.

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