Activation Energies of α-C-Oxidation and N-Oxidation of N-Alkyl-Substituted Amphetamines by Rat Liver Microsomes.: Stereochemistry and Deuterium Isotope Effects

Abstract

1. The effects of temperature on the oxidative degradation of N-isopropyl-amphetamine by rat liver microsomes revealed a great difference in activation energy between the S(+) and R(-) isomers, indicating that different mechanisms are involved.

2. Replacement of the α-H atoms of S(+)-isopropylamphetamine by deuterium caused a marked increase in activation energy (from 11.8 ± 0.9 to 18.6 ± 0.6 kcal/mol) and a decrease in the apparent value of V_max. The deuterium effect indicates that breakage of the α-C-H bond is the rate-limiting step. No isotope effects were found on activation energy or V_max with deuterated R(-)-N-isopropylamphetamine.

3. For the N-dealkylation of N-isopropylphentermine and some N-dialkyl-substituted amphetamines, relatively high activation energies were found, comparable with that for the conversion of the laevo N-isopropylamphetamine (17.9–18.9 kcal/mol).

4. These observations support the suggestion that in the dealkylation and deamination of the secondary amphetamines in the dextro configuration α-C-oxidation is the rate-limiting step. In contrast, the oxidation of the laevo isomers is based on N-oxidation. In the N-dealkylation of tertiary amphetamines stereochemistry is unimportant; a mechanism involving formation of intermediate N-oxides is proposed.