Studies on the mechanism of inhibition of monoamine-oxidase by hydrazine derivatives

Abstract

A comparative study has been made of the inhibition of monoamineoxidase by hydrazine derivatives and of their cupric-ion catalysed decomposition. Both processes require oxygen and both are potentiated by low concentrations of cyanide ions. Several compounds which chelate with cupric ions suppress the catalysed decomposition of hydrazines and reduce the extent of inhibition of monoamine-oxidase produced by 2-phenylisopropylhydrazine or iproniazid. Hydroquinone and 1,2-naphthaquinone-4-sulphonic acid also protect monoamine-oxidase from inhibition by iproniazid but accelerate its cupric-ion catalysed decomposition. Some of these chelating agents and related compounds themselves inhibit monoamine-oxidase. 8-Hydroxyquinoline behaves as a typical competitive inhibitor but inhibition by hydroquinone is largely non-competitive. Inhibition of monoamine-oxidase by hydrazines may also be prevented by 2-phenylisopropylamine, a reversible, competitive monoamine-oxidase inhibitor, which does not affect the catalysed decomposition of hydrazines. The inhibitory activity of 2-phenylisopropylhydrazine is considerably reduced by N-methylation and almost abolished by N′-methylation. N-Alkylation of benzylhydrazine also reduces its inhibitory action. In contrast, N-methylation, N-ethylation or N, N-dimethylation of 2-phenylisopropylamine do not appreciably diminish its monoamine-oxidase inhibitory properties. p-Tolylhydrazine, tert.-butylhydrazine and N-benzylhydroxylamine are irreversible inhibitors of monoamine-oxidase, similar in their kinetic behaviour to arylalkylhydrazines, but less potent. The suggestion that monoamine-oxidase is a copper enzyme in which the copper catalyses the decomposition of hydrazine derivatives in a similar manner to free cupric ions, would explain many of these characteristic features of monoamine-oxidase inhibition.