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), (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.
Yu
H
H
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0815, USA.
Rothman
R B
RB
Dersch
C M
CM
Partilla
J S
JS
Rice
K C
KC
D000818:Animals; D001067:Appetite Depressants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001679:Biogenic Amines / Q000378:metabolism*; D001693:Biological Transport, Active; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D004053:Diethylpropion / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D001067:Appetite Depressants; D001679:Biogenic Amines; D002352:Carrier Proteins; D008024:Ligands; D012701:Serotonin; D004053:Diethylpropion; D004298:Dopamine; D009638:Norepinephrine