![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
NEUROPHARMACOLOGY
Center for Brain Research, Medical University of Vienna, Austria (C.P., A.K., H.R.); Institute of Pharmacognosy, University of Szeged, Hungary (G.N.); and Institute of Organic Chemistry, University of Debrecen, Hungary (S.B., S.A.)
Received February 2, 2005; accepted April 7, 2005.
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
; Green et al., 2003). MDMA was only nonmedically used. Users said the drug made them feel euphoric, more verbal, and closer to other individuals. The typical dosage range of MDMA for recreational use varies from 50 to 150 mg, but the amount per tablet in different batches of tablets may vary 70-fold or more, from almost 0 to well over 100 mg. The ability of MDMA to increase the concentration of serotonin, dopamine, and norepinephrine in the synapse (Johnson et al., 1986; Yamamoto and Spanos, 1988; Fitzgerald and Reid, 1990; Gough et al., 1991; Rothman et al., 2001) probably underlies its production of improved mood and of sensory alterations. However, at higher doses, releasing drugs may cause chemical damage to the cells from which they release neurotransmitters. This damage has been clearly demonstrated in animal experiments with MDMA and related drugs. Chemical studies have shown serotonin content of the brain and serotonin transporter (SERT) uptake or binding still reduced weeks after acute administration of MDMA (Battaglia et al., 1987; Schmidt, 1987; Ricaurte et al., 1988, 1992). In addition, in studies on subhuman primates, highly abnormal reinnervation patterns of serotoninergic axonal sprouting were observed 18 months after MDMA (Fischer et al., 1995).
|
One of the uncertainties in assessing the cause of toxicity in human subjects who have taken MDMA is the purity of the ingested substance. Synthesis of MDMA is relatively simple, and the illegal drug is made in illicit laboratories, with little regard for quality and purity of the product. The impurities can be composed of precursors, intermediates, and byproducts. The amount of these constituents particularly depends on the temperature and time of reaction, the purity of starting materials, and the purification process used for the final product. Since blockade of the SERT by the selective serotonin uptake inhibitors citalopram and fluoxetine prevents not only the acute but also the long-term effects induced by MDMA (Schmidt et al., 1987; Malberg et al., 1996), the excessive neurotransmitter release in serotoninergic and, possibly, dopaminergic neurons seems to be decisive for neurotoxicity. Therefore, we thought that it might be interesting to investigate MDMA synthesis byproducts for potential releasing effects via the human monoamine transporters.
After reviewing the extensive literature related to the clandestine synthesis of amphetamine, methamphetamine, and ecstasy-type compounds, three commonly used synthesis routes, the so called Leukart-Wallach, reductive amination, and bromopropane methods emerged. A number of synthesis impurities specific to these routes were characterized and described by previous authors (Lukaszewski, 1982; Noggle et al., 1991; Bohn et al., 1993; Renton et al., 1993; Palhol et al., 2002). The main precursor or intermediate for the most popular Leucart-Wallach and reductive amination pathways is the benzo[1,3]dioxol-5-yl-propane-2-one (3), which can be prepared from piperonal by the Knoevenagel/nitropropane route (Fig. 1), or from benzo[1,3]dioxol-5-yl-acetic acid (Fig. 2). In the last case, a side reaction produces a diarylacetone (Bohn et al., 1993), which can be transformed to compounds 1,3-bis (3,4-methylenedioxyphenyl)-2-propanamine (12) and N-formyl-1,3-bis (3,4-methylenedioxyphenyl)-prop-2-yl-amine (13) by the Leucart-Wallach pathway (Fig. 2). Because the synthesis of 12 and 13 was not described in the literature, we elaborated a convenient procedure starting from piperonal and using the Knoevenagel method (Fig. 1). Until the late 1990s, the results of the analysis of illicit ecstasy samples seized worldwide expressed the prominence of the Leukart-Wallach and reductive amination routes.
|
; Scholze et al., 2000).
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
).
Synthesis of Substances. The following compounds were prepared according to the described methods, such as 5-(2-nitro-propenyl)-benzo[1,3]dioxole (2) and 2-benzo[1,3]dioxol-5-yl-1-methy-ethylamine (Benington et al., 1958); 3 (Pearl and Beyer, 1951); MDMA (4) (Braun et al., 1980); N-(2-benzo[1,3]dioxol-5-yl-1-methy-ethyl)-N-methyl-formamide (5) and N-(2-benzo[1,3]dioxol-5-yl-1-methy-ethyl)-formamide (8) (Nichols et al., 1986); and 9, 10, and 2-nitro(1,3-bis-benzo[1,3]dioxol-5-yl-propene (11) (Kodukulla et al., 1994) (Fig. 1).
Preparation of N-(2-Benzo[1,3]dioxol-5-yl-1-methy-ethyl)-N-methyl-acetamide (6). A mixture of 1.3 g (6.79 mmol) of 4 acetic anhydride (6 ml) and pyridine (3 ml) was heated at 120°C for 2 h. The mixture was diluted with cold water (100 ml) and extracted with ethyl acetate (3 x 15 ml). The organic solution was concentrated by rotary evaporation and purified by column chromatography (Kieselgel 60, toluene/methanol, 4:1) yield 1.4 g (88.6%) as an oil.
1H NMR (CDCl3) 6.05-6.28 (m, 3, ArH), 5.92 (s, 2, OCH2O), 4.0 (m, 1, CH), 2.85 (s, 3, NCH3), 2.60 (d, 2, CH2), 1.8 (s, 3, COCH3), 1.10 (d, 3, CCH3).
Preparation of 12. A solution of 0.98 g (3.38 mmol) of nitroolefin 11 in 30 ml of benzene was added drop-wise to a stirring suspension of 0.36 g (9.49 mmol) of LiAlH4 in 20 ml of dry Et2O. After the addition, the mixture was heated at reflux on a steam bath for 2.5 h. The excess LiAlH4 was decomposed by slow addition of 1 ml of H2O, and the mixture was filtered through Celite. The ethereal filtrate was extracted with 2 N HCl (3 x 10 ml), and the combined aqueous extracts were basified with NaOH. The free base was extracted with ethyl acetate (3 x 10 ml), dried (MgSO4), filtered, and concentrated by rotary evaporation. The residual oil was dissolved in absolute ethanol, acidified with concentrated HCl, diluted with Et2O, and cooled to yield 0.45 g (41.3%) of white crystalline 12-HCl (melting point, 230-233°C).
1H NMR (CDCl3) 6.61-6.85 (m, 6, ArH), 5.95 (s, 4, OCH2O), 2.75 (dd, 2, CH2), 2.55 (dd, 2, CH2).
Preparation of 13. A solution of 1.09 g (4.0 mmol) of 12-HCl salt dissolved in H2O was neutralized to the free base with excess NaOH. The free base was extracted into ether. The ethereal solution was dried (MgSO4) and filtered, and the ether was removed by rotary evaporation to give the free base as an oil. The oil was dissolved in 30 ml of methyl formate, placed into a 100-ml high-pressure Parr bomb, and heated on steam bath overnight. The bomb was cooled, and the reaction mixture was concentrated by rotary evaporation. The residue was crystallized from ethanol-hexane mixture to give 0.52 g (53%) (melting point, 155-156°C).
1H NMR (CDCl3) 6.55-6.72 (m, 3, ArH), 6.15-6.35 (m, 3, ArH), 6.05 (s, 2, OCH2O), 5.55 (s, 2, OCH2O), 2.75 (dd, 2, CH2), 2.35 (dd, 2, CH2).
The structure of prepared compounds was determined by comparison of their 1H NMR and electron ionization-mass spectroscopy data with those reported in the literature. The synthetic preparation of 12 and 13 has not been reported earlier. These were previously identified as impurities of illegal MDA synthesis in seized ecstasy tablets (Bohn et al., 1993).
Cell Culture. SK-N-MC (human neuroblastoma) and human embryonic kidney (HEK) 293 cells were grown in minimum essential medium with Earle's salts and L-glutamine, 10% heat-inactivated fetal bovine serum, and 50 mg/liter gentamicin. Cells were grown in 100-mm-diameter tissue culture dishes (polystyrene; Falcon; BD Biosciences Discovery Labware, Bedford, MA) at 37°C under an atmosphere of 5% CO2/95% air. The human DAT or NET cDNA was stably expressed in SK-N-MC cells using methods as described recently (Pifl et al., 1996). The human SERT was similarly expressed in HEK 293 cells using the vector pRc/CMV and selection by 1 g/liter G418 in the medium.
Uptake Experiments. The cells were seeded in poly-D-lysinecoated 24-well plates (2 x 105 SK-N-MC or 1 x 105 HEK cells/well; 1 day later, each well was washed with 0.5 ml of uptake buffer and incubated with 0.5 ml of buffer containing various concentrations of the drugs. Uptake was started by addition of [3H]dopamine, [3H]norepinephrine, or [3H]serotonin at a final concentration of 1 µM (specific activity 0.14 Ci/mmol) after 2 min of preincubation. After incubation for 2.5 min at 25°C, it was stopped by aspirating the uptake buffer and washing each well twice with 1 ml of ice-cold buffer. Nonspecific uptake was determined in the presence of 10 µM mazindol (DAT and NET cells) or 3 µM clomipramine (SERT cells). The radioactivity remaining in each well was determined by incubating with 0.4 ml of 1% sodium dodecyl sulfate and transferring this solution into scintillation vials containing 3 ml of scintillation cocktail (Ultima Gold MV; PerkinElmer Life and Analytical Sciences, Boston, MA). The uptake buffer consisted of 4 mM Tris-HCl, 6.25 mM HEPES, 120 mM NaCl, 5 mM KCl, 1.2 mM CaCl2, 1.2 mM MgSO4, 5.6 mM D-glucose, and 0.5 mM ascorbic acid, pH 7.1.
Superfusion Experiments. Cells were seeded onto poly-D-lysine-coated 5-mm-diameter glass cover slips in 96-well tissue culture plates (7 x 104 SK-N-MC cells/well and 3 x 104 HEK cells/well). On the following morning, cells were loaded with [3H] MPP+ in uptake buffer at 37°C: DAT cells, 6 µM with 0.2 Ci/mmol, 20 min; NET cells, 0.1 µM with 29 Ci/mmol, 20 min; and SERT cells, 10 µM with 0.4 Ci/mmol, 30 min. Coverslips were then transferred to small chambers and superfused (25°C, 1.0 ml/min) with the uptake buffer mentioned above in a setup as described recently (Pifl et al., 1995; Scholze et al., 2000). After a washout period of 45 min to establish a stable efflux of radioactivity, the experiment was started with the collection of 4-min fractions. At the end of the experiment, cells were lysed by superfusion with 4 ml of 1% SDS. The radioactivity in the superfusate fractions and the SDS-lysates was determined by liquid scintillation counting. Release of tritium was expressed as fractional rate; i.e., the radioactivity released during a fraction was expressed as percentage of the total radioactivity present in the cells at the beginning of that fraction.
Data Analysis. Uptake data of each separate experiment were fitted to the equation f = min + (max - min)/(1 + xHill slope/IC50Hill slope), min being nonspecific uptake, max the uptake in the absence of inhibiting drug, x the molar concentration of the inhibiting drug, and IC50 the drug concentration that inhibits 50% of specific uptake. Since max and min did not differ significantly from 100% and nonspecific uptake, respectively, they were constrained to these values to accurately estimate IC50 and Hill slope. From the fitted IC50 and Hill slopes of each experiment mean values ± S.D. were calculated. Dose-response dependence of the release stimulation was generated from mean values by fitting the increment over baseline (baseline = mean of the first three fractions) of the 20-min fraction to the equation f = Emax/(EC50 + x), Emax being maximal efflux over baseline, x the molar concentration of MDMA, and EC50 the MDMA concentration that stimulates 50% of maximal efflux. Fitting was performed by the nonlinear curve-fitting computer program SigmaPlot (Systat Software, Inc., Point Richmond, CA). All results were expressed as means ± S.D.
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
|
|
Stimulation of NET-, SERT-, and DAT-Mediated Release by MDMA. To measure carrier-mediated release, we used a technique in which transporter-expressing cells grown on coverslips were prelabeled with the metabolically inert transporter substrate [3H]MPP+ and superfused in micro-chambers. The releasing activity of a drug added to the superfusion buffer was discerned by an increase of radioactivity in the fractionated perfusates. As shown in Fig. 4, MDMA, tested at a concentration of 3 µM, increased [3H]MPP+-efflux from NET-, SERT-, and DAT-expressing cells. This releasing action was transporter-mediated since it was blocked by 10 µM of the NET- and DAT-blocking drug mazindol in NET- and DAT-cells (Fig. 4, A and C, respectively) and by 3 µM of the SERT uptake inhibitor clomipramine in SERT cells (Fig. 4B). MDMA concentration-dependently stimulated release from NET, SERT, and DAT cells (Fig. 5, A-C, respectively), with the highest potency on the NET (EC50, 0.64 ± 0.05 µM; Emax, 9.0 ± 0.26%) and the lowest on the DAT (EC50, 3.2 ± 0.6 µM; Emax, 3.6 ± 0.16%), and a potency on the SERT in between (EC50, 1.1 ± 0.9 µM; Emax, 8.8 ± 0.76%).
|
|
Releasing Activity of Compounds 12 and 13. 12, tested at 10, 30, and 100 µM, had a weak releasing activity on the NET and SERT and slightly decreased efflux from DAT-expressing cells (Fig. 6, A-C, respectively; data on the release by 1 µM MDMA are included for comparison from Fig. 5). There was no clear-cut concentration dependence in the NET and SERT cells. 13 did not affect efflux from cells expressing the NET or SERT in concentrations up to 100 µM and weakly suppressed efflux from DAT-cells at a concentration of 30 and 100 µM (data not shown).
|
|
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
MDMA had a higher affinity to the NET than to the SERT and DAT in our uptake blocking and release experiments, respectively. These findings, obtained on the human transporter proteins, confirm and extend the study by Rothman et al. (2001) in which the most potent effect of amphetamine-type stimulants was to release norepinephrine from rat synaptosomal preparations. It further supports the hypothesis that the action of MDMA on the noradrenergic system might contribute to the subjective effects of MDMA in humans.
Long-term toxicity of ecstasy preparations in humans is a big concern considering the widespread abuse of this drug. Since the discovery of the dramatic effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a byproduct of illegal synthesis of a meperidine analog (Langston, 1985), such potential hazard of the impurities in illegally synthesized ecstasy preparations cannot be ruled out. The clandestine synthesis of MDMA is based foremost on two methods, the Leukart-Wallach (3 
5 MDMA and 3 8 MDMA in Fig. 2) and the reductive amination (3 MDMA in Fig. 1) routes. Of the ecstasy impurities investigated in this study, 5, 8, 12, and 13 relate to the Leukart-Wallach route (Fig. 2), 5 and 8 being intermediates of MDMA synthesis and 12 and 13 being side products of a reaction intended to produce a precursor of this synthetic pathway. Compounds 2 and 6 relate to both routes: 2 is produced as an intermediate of a synthesis (the Knoevenagel/nitropropane route) intended to produce the precursor 3 of both routes, and 6 may be produced as a side product of the final synthetic step to MDMA.
Compounds 2, 5, 6, 8, 12, and 13 have been found in seized samples of illegally synthesized ecstasy preparations. However, there are no quantitative data allowing a reliable estimation of the amounts to be expected in humans taking a street preparation of ecstasy. On the other hand, it is note-worthy that in a reaction analogous to that in Fig. 2, the amount of diarylacetone byproduct in the reaction of phenylacetic acid and acetic acid was reported 20% compared with 70% arylmethyl keton (Herbst and Manske, 1947). Although a separation by fractionated distillation is possible, this is a not too effective method. The ratio of product and byproduct and the separation difficulties may be similar in the synthesis of compound 3, the precursor of the pharmacologically active compounds 12 and 13 that may be consequently in more than just trace amounts in preparations following the Leukart-Wallach route.
There are two reasons why our findings on cultured cells are relevant for the abuse of illegally produced ecstasy by humans. First, even if the ultimate mechanism is still not clarified, a releasing activity is necessary if not sufficient for amphetamine-type neurotoxicity (Baumann et al., 2001), whereas blocking without releasing activity is potentially inhibitory on in vivo effects of amphetamines whether they are acute behavioral or chronic neurotoxic ones (Schmidt et al., 1987; Malberg et al., 1996; Shankaran et al., 1999; Sanchez et al., 2001). 12 had an intrinsic activity in carrier-mediated release that was less than one-tenth of that of MDMA on the NET or SERT and showed no release mediated by the DAT at all. 13, the other substance with reasonable affinity to the monoamine transporters, did not induce release mediated by any of the three transporters. In contrast, 12 and 13 showed properties of straight uptake inhibitors. They blocked the release induced by MDMA in a concentration-dependent manner. The lack of releasing activity rules out a neurotoxic action of the studied ecstasy synthesis by-products, whereas the inhibitory activity of 12 and 13 on MDMA-induced release would actually predict a neuroprotective effect. On the same line, one could expect that 12 and 13 would attenuate the psychological effects of ecstasy in humans consistent with observations that serotonin uptake inhibitors prevent various effects in human volunteers (Stein and Rink, 1999; Liechti et al., 2000). Second, the findings were obtained on the human proteins. This is essential considering the well known species differences of drug interactions with monoamine transporters (Giros et al., 1992; Barker et al., 1994; Paczkowski et al., 1999) and the varying effects of MDMA in different species (for references, see Green et al., 2003).
The investigation of the human versions of the factors that are decisively involved in the in vivo action of amphetamine related compounds is also the major advantage of our transfected cell approach. On the other hand, a homogenous population of cultured cells heterologously expressing proteins cannot replace experiments in animals for obtaining data about neurotoxic effects, although the importance of animal experiments seems to be weakened by the considerable differences in the toxic reaction to MDMA between various species.
A comparison of the interaction of the various ecstasy impurity compounds also gives new insight into structure-activity relationships for drug recognition by the human monoamine transporters. First, effects of modification of the side chain of the 
-phenethylamine structure can be discerned. The amino group in this structure seems to be crucial for affinity to the transporters since 10 with a nitro instead of an amino group had only low affinity. In a recent study addressing structure-activity relationships, all compounds lacking the amino group were weak on the DAT (Appell et al., 2004). N-Alkylation has been reported to slightly impair the interaction of phenylethylamines with norepinephrine and dopamine uptake (Burgen and Iversen, 1965; Horn, 1973). In our study, the formamide or acetamide modification of the amino group strongly reduced the affinity of MDMA to the transporters as can be seen from the weak uptake inhibitory potency of 5 and 6 on uptake of the monoamines. Interestingly, 8, the formamide of 3,4-methylenedioxy-amphetamine, had a negligible affinity at the SERT (as well as at the NET and DAT), whereas the analogous modification of the dimer structure 12 resulted in compound 13, which was equipotent with 12 and MDMA at the SERT and inhibited uptake with an IC50 value in the low micromolar range.
This leads to other intriguing structure-activity findings, namely the transporter interaction of the compounds 12 and 13 containing two 3,4-methylenedioxyphenyl groups compared with that of 3,4-methylenedioxyamphetamine (not functionally different from MDMA; see Wichems et al., 1995), and 8 containing only one of them: the 3,4-methylenedioxy substitution increased the affinity of phenylethylamines to the SERT and decreased it to the NET and DAT (Wall et al., 1995; Rothman et al., 2001). This can explain our finding that 13, containing two 3,4-methylenedioxyphenyl groups, was equipotent with MDMA at the SERT, whereas it displayed less affinity to NET and DAT than MDMA. Nevertheless, it is surprising how the second 3,4-methylenedioxyphenyl groups in 13 restored the transporter affinity by masking the effect of the formamide residue in the simple 3,4-methylenedioxyphenyl derivative 8, which had no transporter affinity. That the formamide structure is unstable and 13 was hydrolyzed to 12 could be ruled out by dissolving 13 immediately before the experiment by the different activity of 13 and 12 on the NET and DAT and by the persistently low potency of 8, which by the same token should have been converted to the potent 3,4-methylenedioxyamphetamine.
Finally, although MDMA is a potent releasing drug on NET, SERT and DAT, the compounds 12 and 13 blocked MDMA-induced release. In a way, the second 3,4-methylenedioxyphenyl group in 12 and 13 seems to switch the mode of interaction with the transporters from induction of transporter-mediated release to transporter inhibition. Based on the concept that a drug acts as a releasing agent by being a transporter substrate that is actively moved from the outside to the inside of the cell, where it exchanges with a different substrate, e.g., neurotransmitter or MPP+ (Fischer and Cho, 1979), the weak or lacking releasing activity of 12 and 13 would suggest that they are poor transporter substrates. This could be simply due to their more bulky structure or more specifically related to the observation that optimal translocation has steric requirements for the amine functionality (Meiergerd and Schenk, 1994), which might be lost in the molecules with two methylenedioxyphenyl groups.
In conclusion, we have found that byproducts of illegal ecstasy synthesis can interact with the primary sites of action of MDMA, the monoamine transporters, and were active with similar potency as MDMA. The mode of interaction, predominantly transport inhibition compared with induction of release, argues against a neurotoxic potential of the substances investigated.
|
Footnotes |
|---|
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: MDMA, N-methyl-3,4-methylenedioxy-amphetamine or 3,4-methylenedioxymethamphetamine; SERT, serotonin transporter; 3, benzo[1,3]dioxol-5-yl-propane-2-one; 12, 1,3-bis (3,4-methylenedioxyphenyl)-2-propanamine; 13, N-formyl-1,3-bis (3,4-methylenedioxyphenyl)-prop-2-yl-amine; 9, 5-(2-nitro-vinyl)-benzo[1,3]dioxole; DAT, dopamine transporter; NET, norepinephrine transporter; MPP+, 1-methyl-4-phenylpyridiniuml; 2, 5-(2-nitro-propenyl)-benzo[1,3]dioxole; 4, MDMA; 5, N-(2-benzo[1,3]dioxol-5-yl-1-methy-ethyl)-N-methyl-formamide; 8, N-(2-benzo[1,3]dioxol-5-yl-1-methy-ethyl)-formamide; 10, 5-(2-nitro-ethyl)-benzo[1,3]dioxole; 11, 2-nitro(1,3-bis-benzo[1,3]dioxol-5-yl-propene; 6, N-(2-benzo[1,3]dioxol-5-yl-1-methy-ethyl)-N-methyl-acetamide; HEK, human embryonic kidney.
Address correspondence to: Dr. Christian Pifl, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria. E-mail: christian.pifl{at}meduniwien.ac.at
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Appell M, Berfield JL, Wang LC, Dunn WJ III, Chen N, and Reith ME (2004) Structure-activity relationships for substrate recognition by the human dopamine transporter. Biochem Pharmacol 67: 293-302.[CrossRef][Medline]
Barker EL, Kimmel HL, and Blakely RD (1994) Chimeric human and rat serotonin transporters reveal domains involved in recognition of transporter ligands. Mol Pharmacol 46: 799-807.[Abstract]
Battaglia G, Yeh SY, O'Hearn E, Molliver ME, Kuhar MJ, and De Souza EB (1987) 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. J Pharmacol Exp Ther 242: 911-916.
Baumann MH, Ayestas MA, Dersch CM, and Rothman RB (2001) 1-(m-Chlorophenyl)piperazine (mCPP) dissociates in vivo serotonin release from long-term serotonin depletion in rat brain. Neuropsychopharmacology 24: 492-501.[CrossRef][Medline]
Benington F, Morin RD, Clark L, and Fox RP (1958) Psychopharmacological activity of ring- and side chain-substituted -phenethylamines. J Org Chem 23: 1979-1983.[CrossRef]
Bohn M, Bohn G, and Blaschke G (1993) Synthesis markers in illegally manufactured 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine. Int J Leg Med 106: 19-23.[CrossRef][Medline]
Braun U, Shulgin T, and Braun G (1980) Centrally active N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (3,4-methylenedioxyamphetamine). J Pharm Sci 69: 192-195.[CrossRef][Medline]
Burgen ASV and Iversen LL (1965) The inhibition of noradrenaline uptake by sympathomimetic amines in the rat isolated heart. Brit J Pharmacol Chemother 25: 34-49.
Fischer C, Hatzidimitriou G, Wlos J, Katz J, and Ricaurte G (1995) Reorganization of ascending 5-HT axon projections in animals previously exposed to the recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). J Neurosci 15: 5476-5485.[Abstract]
Fischer JF and Cho AK (1979) Chemical release of dopamine from striatal homogenates: evidence for an exchange diffusion model. J Pharmacol Exp Ther 208: 203-209.
Fitzgerald JL and Reid JJ (1990) Effects of methylenedioxymethamphetamine on the release of monoamines from rat brain slices. Eur J Pharmacol 191: 217-220.[CrossRef][Medline]
Giros B, el Mestikawy S, Godinot N, Zheng K, Han H, Yang-Feng T, and Caron MG (1992) Cloning, pharmacological characterization and chromosome assignment of the human dopamine transporter. Mol Pharmacol 42: 383-390.[Abstract]
Gough B, Ali SF, Slikker W Jr, and Holson RR (1991) Acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on monoamines in rat caudate. Pharmacol Biochem Behav 39: 619-623.[CrossRef][Medline]
Green AR, Mechan AO, Elliott JM, O'Shea E, and Colado MI (2003) The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). Pharmacol Rev 55: 463-508.
Herbst RM and Manske RH (1947) Methylbenzyl ketone from phenylacetic acid. Org Synt Coll Vol 2: 389-391.
Horn AS (1973) Structure-activity relations for the inhibition of catecholamine uptake into synaptosomes from noradrenaline and dopaminergic neurones in rat brain homogenates. Br J Pharmacol 47: 332-338.[Medline]
Johnson MP, Hoffman AJ, and Nichols DE (1986) Effects of the enantiomers of MDA, MDMA and related analogues on [3H]serotonin and [3H]dopamine release from superfused rat brain slices. Eur J Pharmacol 132: 269-276.[CrossRef][Medline]
Kalant H (2001) The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs. CMAJ 165: 917-928.
Kodukulla RPK, Trivedi GK, Vora D, and Mathur HH (1994) Synthesis, chemical transformation and antimicrobial activity of a novel class of nitroolefins: 1,3-diariyl-2-nitroprop-1-enes. Synth Commun 24: 819-832.
Langston JW (1985) MPTP and Parkinson's disease. Trends Neurosci 8: 79-83.
Liechti ME, Baumann C, Gamma A, and Vollenweider FX (2000) Acute psychological effects of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") are attenuated by the serotonin uptake inhibitor citalopram. Neuropsychopharmacology 22: 513-521.[CrossRef][Medline]
Lukaszewski T (1982) Spectroscopic and chromatographic identification of precursors, intermediates and impurities of 3,4-methylenedioxyamphetamine synthesis. J Assoc Off Anal Chem 61: 951-967.
Malberg JE, Sabol KE, and Seiden LS (1996) Co-administration of MDMA with drugs that protect against MDMA neurotoxicity produces different effects on body temperature in the rat. J Pharmacol Exp Ther 278: 258-267.
Meiergerd SM and Schenk JO (1994) Striatal transporter for dopamine: catechol structure-activity studies and susceptibility to chemical modification. J Neurochem 62: 998-1008.[Medline]
Nichols DE, Hoffman AJ, Oberlender RA, Jacob P 3rd, and Shulgin AT (1986) Derivatives of 1-(1,3-benzodioxol-5-yl)-2-butanamine: representatives of a novel therapeutic class. J Med Chem 29: 2009-2015.[CrossRef][Medline]
Noggle FT, Clark CR, and De Ruiter J (1991) Gas chromatographic and mass spectrometric analysis of samples from clandestine laboratories involved in the synthesis of ecstasy from sassafras oil. J Chrom Sci 29: 168-173.
Paczkowski FA, Bryan-Lluka LJ, Pörzgen P, Brüss M, and Bönisch H (1999) Comparison of the pharmacological properties of cloned rat, human and bovine nor-epinephrine transporters. J Pharmacol Exp Ther 290: 761-767.
Palhol F, Boyer S, Naulet N, and Chabrillat M (2002) Impurity profiling of seized MDMA tablets by capillary gas chromatography. Anal Bioanal Chem 374: 274-281.[CrossRef][Medline]
Pearl JA and Beyer DL (1951) Reactions of vanillin and its derived compounds: XII. Benzyl methyl ketones derived from vanillin and its related compounds. J Org Chem 16: 221-224.[CrossRef]
Pifl C, Drobny H, Reither H, Hornykiewicz O, and Singer EA (1995) Mechanism of the dopamine-releasing actions of amphetamine and cocaine: plasmalemmal dopamine transporter versus vesicular monoamine transporter. Mol Pharmacol 47: 368-373.[Abstract]
Pifl C, Hornykiewicz O, Giros B, and Caron MG (1996) Catecholamine transporters and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity: studies comparing the cloned human noradrenaline and human dopamine transporter. J Pharmacol Exp Ther 277: 1437-1443.
Renton RJ, Cowie JS, and Oon MCH (1993) A study of the precursors, intermediates and reaction by-products in the synthesis of 3,4-methylenedioxymethylamphetamine and its application to forensic drug analysis. Forensic Sci Int 60: 189-202.[CrossRef][Medline]
Ricaurte GA, Forno LS, Wilson MA, DeLanney LE, Irwin I, Molliver ME, and Langston JW (1988) (+/-)3,4-methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates. J Am Med Assoc 260: 51-55.
Ricaurte GA, Martello AL, Katz JL, and Martello MB (1992) Lasting effects of (+-)-3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic neurons in nonhuman primates: neurochemical observations. J Pharmacol Exp Ther 261: 616-622.
Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, and Partilla JS (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39: 32-41.[CrossRef][Medline]
Sanchez V, Camarero J, Esteban B, Peter MJ, Green AR, and Colado MI (2001) The mechanisms involved in the long-lasting neuroprotective effect of fluoxetine against MDMA ("ecstasy")-induced degeneration of 5-HT nerve endings in rat brain. Br J Pharmacol 134: 46-57.[CrossRef][Medline]
Schmidt CJ (1987) Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. J Pharmacol Exp Ther 240: 1-7.
Schmidt CJ, Levin JA, and Lovenberg W (1987) In vitro and in vivo neurochemical effects of methylenedioxymethamphetamine on striatal monoaminergic systems in the rat brain. Biochem Pharmacol 36: 747-755.[CrossRef][Medline]
Scholze P, Zwach J, Kattinger A, Pifl C, Singer EA, and Sitte HH (2000) Transporter-mediated release: a superfusion study on human embryonic kidney cells stably expressing the human serotonin transporter. J Pharmacol Exp Ther 293: 870-878.
Shankaran M, Yamamoto BK, and Gudelsky GA (1999) Mazindol attenuates the 3,4-methylenedioxymethamphetamine-induced formation of hydroxyl radicals and long-term depletion of serotonin in the striatum. J Neurochem 72: 2516-2522.[CrossRef][Medline]
Stein DJ and Rink J (1999) Effects of "Ecstasy" blocked by serotonin reuptake inhibitors. J Clin Psychiatry 60: 485.
Wall SC, Gu H, and Rudnick G (1995) Biogenic amine flux mediated by cloned transporters stably expressed in cultured cell lines: amphetamine specificity for inhibition and efflux. Mol Pharmacol 47: 544-550.[Abstract]
Wichems CH, Hollingsworth CK, and Bennett BA (1995) Release of serotonin induced by 3,4-methylenedioxymethamphetamine (MDMA) and other substituted amphetamines in cultured fetal raphe neurons: further evidence for calcium-independent mechanisms of release. Brain Res 695: 10-18.[CrossRef][Medline]
Yamamoto BK and Spanos LJ (1988) The acute effects of methylenedioxymethamphetamine on dopamine release in the awake-behaving rat. Eur J Pharmacol 148: 195-203.[CrossRef][Medline]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
