Uptake and release effects of diethylpropion and its metabolites with biogenic amine transporters

Three metabolites of diethylpropion (1), (+/-)-2-ethylamino-1-phenyl-propan -1-one (2), (1 R,2S)-(-)-N,N-diethylnorephedrine (3a) and (1S,2R)-(-)-N,N-d iethylnorephedrine (3b) were synthesized. Their uptake and release effects with biogenic amine transporters were evaluated. A major finding of this st udy is that the in vivo activity of diethylpropion on biogenic amine transp orters is most likely due to metabolite 2 as diethylpropion (1) and the met abolites 3a and 3b showed little or no effect in the assays studied. These studies also revealed that 2 acted as a substrate at the norepinephrine (IC 50=99nM) and serotonin transporters (IC50 = 2118 nM) and an uptake inhibito r at the dopamine transporter (IC50 = 1014 nM). The potent action of 2 at t he NE transporter supports the hypothesis that amphetamine-type subjective effects may be mediated in part by brain norepinephrine. (C) 2000 Published by Elsevier Science Ltd.