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

H Yu, R B Rothman, C M Dersch, J S Partilla, K C Rice

Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0815, USA.

Bioorganic & medicinal chemistry 2000 Dec

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Three metabolites of diethylpropion (1), (+/-)-2-ethylamino-1-phenyl-propan-1-one (2), (1R,2S)-(-)-N,N-diethylnorephedrine (3a) and (1S,2R)-(-)-N,N-diethylnorephedrine (3b) were synthesized. Their uptake and release effects with biogenic amine transporters were evaluated. A major finding of this study is that the in vivo activity of diethylpropion on biogenic amine transporters is most likely due to metabolite 2 as diethylpropion (1) and the metabolites 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 (IC50 = 99 nM) and serotonin transporters (IC50 = 2118 nM) and an uptake inhibitor at the dopamine transporter (IC50 = 1014 nM). The potent action of 2 at the NE transporter supports the hypothesis that amphetamine-type subjective effects may be mediated in part by brain norepinephrine.

Citation

H Yu, R B Rothman, C M Dersch, J S Partilla, K C Rice. Uptake and release effects of diethylpropion and its metabolites with biogenic amine transporters. Bioorganic & medicinal chemistry. 2000 Dec;8(12):2689-92