NEWER APPROACH TO THE ELECTRONIC STRUCTURE OF CHOLINESTERASE INHIBITORS

Abstract

It is one of the most fundamental problems not only in the enzymological but also in the pharmacological researches to consider quantum-chemically the interaction between an enzyme and its inhibitor on the molecular basis. The author has recently extensively studied on the relation between electronic structure of phenylacetate derivatives and their rates to be hydrolyzed by the cholinesterase (1); though this paper deals partially with those results, it is confined at present to the problem on the relationship between the electronic structure and inhibiting force of cholinesterase inhibitors. A competitive inhibition seems to be of a simpler reaction type and such a secondary effect as the molecular deformation to be derived from the drug absorption may be also easily excluded, so it would be the most favorable object for the present experimentation. Wilson et al. (2) showed the development of competitive inhibition between cholinesterase and various phenyltrimethylammonium derivatives assuming it as derived from the hydrogen-bonding of the esteratic site of cholinesterase to phenylhydroxyl group of those derivatives, and they also emphasized that in order to determine the inhibiting force in those reaction systems the spacial arrangement of molecules or molecular complimentariness was more important factor than the chemical change thereby exerted. They added, however, that the significance of chemical change as a cause of the inhibiting force could not be entirely avoided, and they attributed the weakness in the inhibiting force of 2-hydroxybenzyl.trime thylammoniurn bromide (compound No. 8 in Table 1) to the larger value of pKa than that of 3 hydroxypheny.ltrimethylammonium salts, all of which, however, were the same in spacial distance from the quaternary ammonium radical to the hydroxyl group and from the esteratic site to the anionic site of cholinesterase. But if it might be true, there is a discrepancy for the fact that the pKa value of the compound No. 8 is 8.7 which is weaker in the inhibiting force than the compound No. 5, that is 6-methoxy-3-hydroxyphenyltriniethylammonium chloride, the pKa value (8.6) of the latter being, however, almost as large as that of the compound No. 8. Thus, it is clear that there is at least no intimate connection between the pKa value and inhibiting force in the case of 3-hydroxyphenylmethylammonium derivatives. According to Wilson et al. (2) the fact that 2.9 kcal of free energy change resulted from the KI ratio of the compound No. 1 vs. the compound No. 6 was just coincided to what was brought about by the hydrogen-bonding in this reaction appeared to give some support to their hydrogen-bonding hypothesis. But neither this energy change would necessarily brought about by the hydrogen-bonding nor this phenomenon would be characteristic of the hydrogen-bonding. In the author's opinion there should be three possibilities to be taken into consideration in order to interpret this phenomenon quantum-chemically which are as follows : (i) There would be the formation of charge transfer complex or some substitution reaction, instead of the hydrogen-bonding. (ii) There would be surely the hydrogen-bonding, the pKa value being, however, no appropriate decisive index. (iii) Apart from the hydrogen-bonding, there would be some other forces, e.g., van der Waals', contributable to the reaction.