Metabolism of N,N-dialkylated amphetamines, including deprenyl, by CYP2D6 expressed in a human cell line

1. Five N,N-dialkylated amphetamines, N-methyl-N-propargylamphetamine (depr enyl; DEP), N-benzyl-N-methylamphetamine (benzphetamine; BPA), N-allyl-N-me thylamphetamine (AMA), N,N-diallylamphetamine (DAA) and N-methyl-N-propylam phetamine (MPA), were metabolized in vitro with a microsomal preparation fr om cells expressing human CYP2D6 to determine what influence the N,N-dialky l substituents had on the extent of N-dealkylation and/or aromatic ring oxi dation. 2. The results obtained from experiments with the first two substrates, DEP and BPA, were surprisingly different. Whereas DEP was N-demethylated and N -depropargylated by the CYP2D6 enzyme system, no metabolites were formed fr om BPA. Subsequently, it was determined that AMA, DAA and MPA also underwen t CYP2D6-catalysed N-dealkylation. Both N-methyl- and N-allylamphetamine we re identified as products of AMA metabolism; similarly, metabolism of MPA p roduced both N-methyl- and N-propargylamphetamine, and N-allylamphetamine w as the sole metabolite of DAA. 3. No N,N-didealkylated product (i.e. amphetamine) was isolated from incuba tes of any of the five substrates, and none of the N,N-dialkylated substrat es was metabolized to a ring-hydroxylated product. 4. Rates of these CYP2D6-catalysed reactions were dependent on the nature a nd degree of unsaturation of the N-substituents.