Cytochrome P-450 complex formation in the metabolism of phenylalkylamines. 8. Stereoselectivity in metabolic intermediary complex formation with a series of chiral 2-substituted 1-phenyl-2-aminoethanes

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Abstract
The formation of cytochrome P-450 metabolic intermediary (MI) complexes from the enantiomers of four 2-alkyl-substituted 1-phenyl-2-aminoethanes was investigated during NADPH-dependent metabolism in liver microsomes from phenobarbital-pretreated rats. The 2-alkyl substituents were methyl (amphetamine), ethyl, n-propyl and n-butyl groups. The chiral amines were prepared from the corresponding alkyl benzyl ketones by asymmetric hydrogenolytic transamination. Circular dichroism analysis showed that all the amines possessed the S-(+) and R-(-) configuration. The maximal velocity (Vmax(obsd)) of complex formation increased with increasing size of the alkyl group, and for each series of enantiomers a good correlation was obtained between log Vmax(obd) and the logarithm of the octanol/buffer partition coefficient of the substrates. With increasing lipophilicity, the S-(+) enantiomers became more active than the R-(-) isomers in generating the complex. The rates of complex formation for the faster S-(+) enantiomers coincided with those of the previously investigated racemates, indicating that the R-(-) enantiomers do not act as competitive enzyme inhibitors in the rat liver preparations. A stereoselectivity in cytochrome P-450 MI complex formation by 1-phenyl-2-aminoethanes was established. Detection of such differences is dependent on the intrinsic activity of the compound.