Effect of α-Methylation on Inactivation of Monoamine Oxidase by N-Cyclopropylbenzylamine

Richard B Silverman*

*Corresponding author for this work

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43 Scopus citations

Abstract

Monoamine oxidase (MAO) was shown previously [Silverman, R. B., & Hoffman, S. J. (1980) J. Am. Chem. Soc. 102, 7126-7128] to catalyze the oxidation of A-cyclo-propylbenzylamine (N-CBA) at two sites on the molecule. Oxidation at the benzyl methylene gave benzaldehyde and cyclopropylamine; oxidation of the cyclopropyl group, which involved cyclopropyl ring cleavage, led to inactivation of the enzyme. In this paper it is shown that methylation of the benzyl methylene dramatically alters this partition ratio in favor of enzyme inactivation. Contrary to a previous report [Alies, G., & Heegaard, E. V. (1943) J. Biol. Chem. 147, 487-503], it is shown here that α-methylbenzylamine is a substrate for MAO; consequently, N-cyclopropyl-α-methylbenzylamine (N-CαMBA) is a good candidate for mechanism-based inactivation. N-Cyclopropyl[7-14C]benzylamine, N-cyclopropyl-α-methyl [phenyl- 14C] benzylamine, N- [1-3H] -cyclopropylbenzylamine, and N-[1-3H]cyclopropyl-α-methylbenzylamine are synthesized, and product formation following MAO inactivation is quantified. The results obtained with these compounds indicate that with N-CαMBA, α-methylbenzyl oxidation (which produces acetophenone and cyclopropylamine) is only 1% that of cyclopropyl oxidation (which gives enzyme inactivation), whereas with N-CBA the amount of oxidation at the corresponding sites is equal. It also is shown that the Ki values for (R)-(+)- and {S)-{-)-α-methylbenzylamine are similar, suggesting that dimethylation of N-CBA should not interfere with binding to MAO. N-Cyclopropyl-α,α-dimethylbenzylamine, which should be incapable of benzyl oxidation, is prepared and shown to be a mechanism-based inhibitor of MAO whose properties differ slightly from those of N-CBA and N-CαMBA. These results show that α-substitution of N-CBA has a profound effect on the partition ratio and present a new approach to rational drug design based on physical organic chemical principles.

Original languageEnglish (US)
Pages (from-to)5206-5213
Number of pages8
JournalBiochemistry
Volume23
Issue number22
DOIs
StatePublished - Jan 1 1984

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ASJC Scopus subject areas

  • Biochemistry

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