PMID- 15831439 OWN - NLM STAT- MEDLINE DCOM- 20050826 LR - 20221207 IS - 0022-3565 (Print) IS - 0022-3565 (Linking) VI - 314 IP - 1 DP - 2005 Jul TI - Pharmacological characterization of ecstasy synthesis byproducts with recombinant human monoamine transporters. PG - 346-54 AB - 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. FAU - Pifl, Christian AU - Pifl C AD - Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria. christian.pifl@meduniwien.ac.at FAU - Nagy, Gabor AU - Nagy G FAU - Berenyi, Sandor AU - Berenyi S FAU - Kattinger, Alexandra AU - Kattinger A FAU - Reither, Harald AU - Reither H FAU - Antus, Sandor AU - Antus S LA - eng PT - Journal Article DEP - 20050414 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (Biogenic Monoamines) RN - 0 (Carrier Proteins) RN - 0 (Dopamine Plasma Membrane Transport Proteins) RN - 0 (Dopamine Uptake Inhibitors) RN - 0 (Hallucinogens) RN - 0 (Indicators and Reagents) RN - 0 (Membrane Glycoproteins) RN - 0 (Membrane Transport Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (Norepinephrine Plasma Membrane Transport Proteins) RN - 0 (Recombinant Proteins) RN - 0 (SLC6A2 protein, human) RN - 0 (SLC6A3 protein, human) RN - 0 (SLC6A4 protein, human) RN - 0 (Serotonin Plasma Membrane Transport Proteins) RN - 0 (Serotonin Uptake Inhibitors) RN - 0 (Symporters) RN - C56709M5NH (Mazindol) RN - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine) RN - NUV44L116D (Clomipramine) SB - IM MH - Biogenic Monoamines/*metabolism MH - Carrier Proteins/*drug effects MH - Cell Line MH - Clomipramine/pharmacology MH - Dopamine Plasma Membrane Transport Proteins MH - Dopamine Uptake Inhibitors/pharmacology MH - Hallucinogens/chemistry/pharmacokinetics/*pharmacology MH - Humans MH - Indicators and Reagents MH - Kinetics MH - Magnetic Resonance Spectroscopy MH - Mazindol/pharmacology MH - Membrane Glycoproteins/metabolism MH - Membrane Transport Proteins/metabolism MH - N-Methyl-3,4-methylenedioxyamphetamine/*analogs & derivatives/pharmacokinetics/*pharmacology MH - Nerve Tissue Proteins/metabolism MH - Norepinephrine Plasma Membrane Transport Proteins MH - Recombinant Proteins/drug effects MH - Serotonin Plasma Membrane Transport Proteins MH - Selective Serotonin Reuptake Inhibitors/pharmacology MH - Structure-Activity Relationship MH - Symporters/metabolism EDAT- 2005/04/16 09:00 MHDA- 2005/08/27 09:00 CRDT- 2005/04/16 09:00 PHST- 2005/04/16 09:00 [pubmed] PHST- 2005/08/27 09:00 [medline] PHST- 2005/04/16 09:00 [entrez] AID - jpet.105.084426 [pii] AID - 10.1124/jpet.105.084426 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2005 Jul;314(1):346-54. doi: 10.1124/jpet.105.084426. Epub 2005 Apr 14.