Pifl C, Nagy G, Berenyi S, Kattinger A, Reither H, Antus S.
Pharmacological characterization of ecstasy synthesis by-products with recombinant human monoamine transporters.
J Pharmacol Exp Ther. 2005 Apr 14; [Epub ahead of print]
Center for Brain Research, Medical University of Vienna, Austria.
Ecstasy samples often contain by-products of the illegal, uncontrolled synthesis of 3,4-methylenedioxy-methamphetamine (MDMA). MDMA and eight chemically defined by-products 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 (NET, SERT and 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 [(3)H]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 a 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 by-products and provide interesting structure-activity relationships on the transporters.
