Pharmacological characterization of ecstasy synthesis byproducts with recombinant human monoamine transporters.
Ecstasy samples often contain byproducts of the illegal, uncontrolled synthesis of N-methyl-3,4-methylenedioxy-amphetamine or 3,4-methylenedioxymethamphetamine (MDMA). MDMA and eight chemically defined byproducts of MDMA synthesis were investigated for their interaction with the primary sites of action of MDMA, namely the human plasmalemmal monamine transporters for norepinephrine, serotonin, and dopamine [(norepinephrine transporter (NET), serotonin transporter (SERT), and dopamine transporter (DAT)]. SK-N-MC neuroblastoma and human embryonic kidney cells stably transfected with the transporter cDNA were used for uptake and release experiments. Two of the eight compounds, 1,3-bis (3,4-methylenedioxyphenyl)-2-propanamine (12) and N-formyl-1,3-bis (3,4-methylenedioxyphenyl)-prop-2-yl-amine (13) had uptake inhibitory potencies with IC50 values in the low micromolar range similar to MDMA. Compounds with nitro instead of amino groups and a phenylethenyl instead of a phenylethyl structure or a formamide or acetamide modification had IC50 values beyond 100 microM. MDMA, 12, and 13 were examined for induction of carrier-mediated release by superfusion of transporter expressing cells preloaded with the metabolically inert transporter substrate [3H]1-methyl-4-phenylpyridinium. MDMA induced release mediated by NET, SERT, or DAT with EC50 values of 0.64, 1.12, and 3.24 microM, respectively. 12 weakly released from NET- and SERT-expressing cells with maximum effects less than one-tenth of that of MDMA and did not release from DAT cells. 13 had no releasing activity. 12 and 13 inhibited release induced by MDMA, and the concentration dependence of this effect correlated with their uptake inhibitory potency at the various transporters. These results do not support a neurotoxic potential of the examined ecstasy synthesis byproducts and provide interesting structure-activity relationships on the transporters.
Pifl
Christian
C
Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria. christian.pifl@meduniwien.ac.at
Nagy
Gabor
G
Berényi
Sándor
S
Kattinger
Alexandra
A
Reither
Harald
H
Antus
Sándor
S
D015306:Biogenic Monoamines / Q000378:metabolism*; D002352:Carrier Proteins / Q000187:drug effects*; D002460:Cell Line; D002997:Clomipramine / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D006213:Hallucinogens / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008454:Mazindol / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011994:Recombinant Proteins / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D027981:Symporters / Q000378:metabolism
D015306:Biogenic Monoamines; D002352:Carrier Proteins; D002997:Clomipramine; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D006213:Hallucinogens; D007202:Indicators and Reagents; D008454:Mazindol; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011994:Recombinant Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; C493227:SLC6A2 protein, human; C493214:SLC6A3 protein, human; C493230:SLC6A4 protein, human