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 (deprenyl; DEP), N-benzyl-N-methylamphetamine (benzphetamine; BPA), N-allyl-N-methylamphetamine (AMA), N,N-diallylamphetamine (DAA) and N-methyl-N-propylamphetamine (MPA), were metabolized in vitro with a microsomal preparation from cells expressing human CYP2D6 to determine what influence the N,N-dialkyl substituents had on the extent of N-dealkylation and/or aromatic ring oxidation. 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 from BPA. Subsequently, it was determined that AMA, DAA and MPA also underwent CYP2D6-catalysed N-dealkylation. Both N-methyl- and N-allylamphetamine were identified as products of AMA metabolism; similarly, metabolism of MPA produced both N-methyl- and N-propargylamphetamine, and N-allylamphetamine was the sole metabolite of DAA. 3. No N,N-didealkylated product (i.e. amphetamine) was isolated from incubates of any of the five substrates, and none of the N,N-dialkylated substrates was metabolized to a ring-hydroxylated product. 4. Rates of these CYP2D6-catalysed reactions were dependent on the nature and degree of unsaturation of the N-substituents.
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Neurochemical Research Unit, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Coutts
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D000661:Amphetamine / Q000378:metabolism; D000662:Amphetamines / Q000378:metabolism*; D001589:Benzphetamine / Q000378:metabolism; D002460:Cell Line; D002849:Chromatography, Gas; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008694:Methamphetamine / Q000378:metabolism; D008745:Methylation; D008861:Microsomes / Q000378:metabolism; D008956:Models, Chemical; D012642:Selegiline / Q000378:metabolism*; D014162:Transfection
D000662:Amphetamines; C408562:N-methyl-N-propyl amphetamine; D001589:Benzphetamine; D012642:Selegiline; D008694:Methamphetamine; D000661:Amphetamine; D019389:Cytochrome P-450 CYP2D6