Cytochrome P-455 nm complex formation in the metabolism of phenylalkylamines. XIII. Enzyme interactions with a series of beta-alkyl-substituted 2-phenylethanamines and corresponding N-hydroxylamines.

Abstract

The formation of Metabolic Intermediate (MI) complexes from a series of beta-alkylsubstituted 2-phenylethanamines and corresponding N-hydroxylamines is investigated during NADPH-dependent metabolism in liver microsomes from phenobarbital pretreated rats. The beta-alkyl substituents are methyl, dimethyl, ethyl, di-ethyl, n-propyl, di-n-propyl and i-propyl groups. The amines are synthesized by LiAlH4-reduction of the corresponding nitriles, which are prepared through alkylation of the enolate anion of phenylacetonitrile. The hydroxylamines are prepared either by oxidation of the corresponding benzylimines with m-chloroperbenzoic acid and subsequent hydrolysis of the initially formed 3-phenyloxaziridines, or by H2O2-mediated oxidation of the corresponding amines in the presence of catalytic amounts of sodium tungstate, followed by reduction with cyanoborohydride. The amines are found to be completely devoid of complexing activity, while the hydroxylamines form the MI complex at high rates. Complex formation from these substrates thus parallels the known behaviour of 2-phenylethanamine and its corresponding N-hydroxylamine. Since N-oxygenation is known to be a prerequisite for MI complex formation from amines our results suggest that the beta-alkylated 2-phenylethanamines are metabolized exclusively through other pathways. In accordance with this hypothesis, capillary GC-analysis of the incubation mixture of 2-phenylpropanamine shows no formation of N-hydroxylated metabolites; only 2-phenylpropanol, a metabolite formed through the deamination pathway, is found.