DT-Web

DB01454 - 3,4-Methylenedioxymethamphetamine


Identification
Name 3,4-Methylenedioxymethamphetamine
Accession Number DB01454
Type small molecule
Description An N-substituted amphetamine analog. It is a widely abused drug classified as a hallucinogen and causes marked, long-lasting changes in brain serotonergic systems. It is commonly referred to as MDMA or ecstasy. [PubChem]
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 193.2423
Groups illicit
Monoisotopic Weight 193.110278729
Pharmacology
Indication Clinical trials are now testing the therapeutic potential of MDMA for post-traumatic stress disorder (PTSD) and anxiety associated with terminal cancer. MDMA is one of the four most widely used illicit drugs in the U.S.
Mechanism of action It enters neurons via carriage by the monoamine transporters. Once inside, MDMA inhibits the vesicular monoamine transporter, which results in increased concentrations of serotonin, norepinephrine, and dopamine into the cytoplasm, and induces their release by reversing their respective transporters through a process known as phosphorylation. It also acts as a weak 5-HT1 and 5-HT2 receptor agonist. MDMA's unusual entactogenic effects have been hypothesized to be, at least partly, the result of indirect oxytocin secretion via activation of the serotonin system. Oxytocin is a hormone released following events like hugging, orgasm, and childbirth, and is thought to facilitate bonding and the establishment of trust. Based on studies in rats, MDMA is believed to cause the release of oxytocin, at least in part, by both directly and indirectly agonizing the serotonin 5-HT1A receptor.
Absorption Not Available
Protein binding Not Available
Biotransformation Hepatic: CYP450 extensively involved, especially CYP2D6 MDMA is known to be metabolized by two main metabolic pathways: (1) O-demethylenation followed by catechol-O-methyltransferase (COMT)-catalyzed methylation and/or glucuronide/sulfate conjugation; and (2) N-dealkylation, deamination, and oxidation to the corresponding benzoic acid derivatives conjugated with glycine. The metabolism may be primarily by cytochrome P450 (CYP450) enzymes (CYP2D6 (in humans, but CYP2D1 in mice), and CYP3A4) and COMT. Complex, nonlinear pharmacokinetics arise via autoinhibition of CYP2D6 and CYP2D8, resulting in zeroth order kinetics at higher doses. It is thought that this can result in sustained and higher concentrations of MDMA if the user takes consecutive doses of the drug.
Route of elimination renal
Toxicity Not Available
Affected organisms Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available

Targets


Sodium-dependent serotonin transporter
Name Sodium-dependent serotonin transporter
Gene Name SLC6A4
Pharmacological action yes
Actions negative modulator
References
  • Shankaran M, Yamamoto BK, Gudelsky GA: Involvement of the serotonin transporter in the formation of hydroxyl radicals induced by 3,4-methylenedioxymethamphetamine. Eur J Pharmacol. 1999 Dec 3;385(2-3):103-10. - Pubmed
  • Whitworth TL, Herndon LC, Quick MW: Psychostimulants differentially regulate serotonin transporter expression in thalamocortical neurons. J Neurosci. 2002 Jan 1;22(1):RC192. - Pubmed
  • Szabo Z, McCann UD, Wilson AA, Scheffel U, Owonikoko T, Mathews WB, Ravert HT, Hilton J, Dannals RF, Ricaurte GA: Comparison of (+)-(11)C-McN5652 and (11)C-DASB as serotonin transporter radioligands under various experimental conditions. J Nucl Med. 2002 May;43(5):678-92. - Pubmed
  • Boot BP, Mechan AO, McCann UD, Ricaurte GA: MDMA- and p-chlorophenylalanine-induced reduction in 5-HT concentrations: effects on serotonin transporter densities. Eur J Pharmacol. 2002 Oct 25;453(2-3):239-44. - Pubmed
  • Saldana SN, Barker EL: Temperature and 3,4-methylenedioxymethamphetamine alter human serotonin transporter-mediated dopamine uptake. Neurosci Lett. 2004 Jan 16;354(3):209-12. - Pubmed
  • Bogen IL, Haug KH, Myhre O, Fonnum F: Short- and long-term effects of MDMA ( - ecstasy
DTHybrid score 0.5439
Synaptic vesicular amine transporter
Name Synaptic vesicular amine transporter
Gene Name SLC18A2
Pharmacological action yes
Actions inhibitor
References
  • Biezonski DK, Meyer JS: Effects of 3,4-methylenedioxymethamphetamine (MDMA) on serotonin transporter and vesicular monoamine transporter 2 protein and gene expression in rats: implications for MDMA neurotoxicity. J Neurochem. 2010 Feb;112(4):951-62. Epub 2009 Nov 30. - Pubmed
  • Hansen JP, Riddle EL, Sandoval V, Brown JM, Gibb JW, Hanson GR, Fleckenstein AE: Methylenedioxymethamphetamine decreases plasmalemmal and vesicular dopamine transport: mechanisms and implications for neurotoxicity. J Pharmacol Exp Ther. 2002 Mar;300(3):1093-100. - Pubmed
DTHybrid score 0.6277
Sodium-dependent dopamine transporter
Name Sodium-dependent dopamine transporter
Gene Name SLC6A3
Pharmacological action unknown
Actions negative modulator
References
  • Hansen JP, Riddle EL, Sandoval V, Brown JM, Gibb JW, Hanson GR, Fleckenstein AE: Methylenedioxymethamphetamine decreases plasmalemmal and vesicular dopamine transport: mechanisms and implications for neurotoxicity. J Pharmacol Exp Ther. 2002 Mar;300(3):1093-100. - Pubmed
  • Fitzgerald JL, Reid JJ: Effects of methylenedioxymethamphetamine on the release of monoamines from rat brain slices. Eur J Pharmacol. 1990 Nov 27;191(2):217-20. - Pubmed
  • Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR: New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol. 2007;47:681-98. - Pubmed
DTHybrid score 0.6236
5-hydroxytryptamine 2A receptor
Name 5-hydroxytryptamine 2A receptor
Gene Name HTR2A
Pharmacological action unknown
Actions agonist
References
  • Lyon RA, Glennon RA, Titeler M: 3,4-Methylenedioxymethamphetamine (MDMA): stereoselective interactions at brain 5-HT1 and 5-HT2 receptors. Psychopharmacology (Berl). 1986;88(4):525-6. - Pubmed
  • Nash JF, Roth BL, Brodkin JD, Nichols DE, Gudelsky GA: Effect of the R(-) and S(+) isomers of MDA and MDMA on phosphatidyl inositol turnover in cultured cells expressing 5-HT2A or 5-HT2C receptors. Neurosci Lett. 1994 Aug 15;177(1-2):111-5. - Pubmed
DTHybrid score 0.3616
5-hydroxytryptamine 2B receptor
Name 5-hydroxytryptamine 2B receptor
Gene Name HTR2B
Pharmacological action unknown
Actions agonist
References
  • Lyon RA, Glennon RA, Titeler M: 3,4-Methylenedioxymethamphetamine (MDMA): stereoselective interactions at brain 5-HT1 and 5-HT2 receptors. Psychopharmacology (Berl). 1986;88(4):525-6. - Pubmed
DTHybrid score 0.2616
5-hydroxytryptamine 2C receptor
Name 5-hydroxytryptamine 2C receptor
Gene Name HTR2C
Pharmacological action unknown
Actions agonist
References
  • Nash JF, Roth BL, Brodkin JD, Nichols DE, Gudelsky GA: Effect of the R(-) and S(+) isomers of MDA and MDMA on phosphatidyl inositol turnover in cultured cells expressing 5-HT2A or 5-HT2C receptors. Neurosci Lett. 1994 Aug 15;177(1-2):111-5. - Pubmed
  • Lyon RA, Glennon RA, Titeler M: 3,4-Methylenedioxymethamphetamine (MDMA): stereoselective interactions at brain 5-HT1 and 5-HT2 receptors. Psychopharmacology (Berl). 1986;88(4):525-6. - Pubmed
DTHybrid score 0.3153
Sodium-dependent noradrenaline transporter
Name Sodium-dependent noradrenaline transporter
Gene Name SLC6A2
Pharmacological action yes
Actions negative modulator
References
  • Sulzer D, Sonders MS, Poulsen NW, Galli A: Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol. 2005 Apr;75(6):406-33. - Pubmed
  • Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR: New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol. 2007;47:681-98. - Pubmed
  • Haughey HM, Brown JM, Wilkins DG, Hanson GR, Fleckenstein AE: Differential effects of methamphetamine on Na(+)/Cl(-)-dependent transporters. Brain Res. 2000 Apr 28;863(1-2):59-65. - Pubmed
DTHybrid score 0.6727

Transporters


Sodium-dependent noradrenaline transporter
Name Sodium-dependent noradrenaline transporter
Gene Name SLC6A2
Actions Not Available
References
  • Verrico CD, Miller GM, Madras BK: MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment. Psychopharmacology (Berl). 2007 Jan;189(4):489-503. Epub 2005 Oct 12. - Pubmed
DTHybrid score 0.6727
Sodium-dependent dopamine transporter
Name Sodium-dependent dopamine transporter
Gene Name SLC6A3
Actions Not Available
References
  • Verrico CD, Miller GM, Madras BK: MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment. Psychopharmacology (Berl). 2007 Jan;189(4):489-503. Epub 2005 Oct 12. - Pubmed
DTHybrid score 0.6236
Sodium-dependent serotonin transporter
Name Sodium-dependent serotonin transporter
Gene Name SLC6A4
Actions Not Available
References
  • Verrico CD, Miller GM, Madras BK: MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment. Psychopharmacology (Berl). 2007 Jan;189(4):489-503. Epub 2005 Oct 12. - Pubmed
DTHybrid score 0.5439

Predictions


Id Partner name Gene Name Score
4119 Cytochrome P450 2D6 CYP2D6 0.318
556 Alpha-1A adrenergic receptor ADRA1A 0.2216
831 D(2) dopamine receptor DRD2 0.1871
318 Alpha-2A adrenergic receptor ADRA2A 0.1813
4512 Cytochrome P450 3A4 CYP3A4 0.1812
320 5-hydroxytryptamine 1A receptor HTR1A 0.1417
23 D(1A) dopamine receptor DRD1 0.1388
1636 Trace amine-associated receptor 1 TAAR1 0.1338
3941 Amine oxidase [flavin-containing] A MAOA 0.1228
492 Histamine H1 receptor HRH1 0.1195
4200 Cytochrome P450 1A2 CYP1A2 0.1164
632 Alpha-1B adrenergic receptor ADRA1B 0.1139
1588 Multidrug resistance protein 1 ABCB1 0.1135
629 Alpha-2B adrenergic receptor ADRA2B 0.112
378 Alpha-2C adrenergic receptor ADRA2C 0.1074
3939 Amine oxidase [flavin-containing] B MAOB 0.1001
103 Muscarinic acetylcholine receptor M1 CHRM1 0.0989
638 D(3) dopamine receptor DRD3 0.0913
6016 Cytochrome P450 2C19 CYP2C19 0.089
725 5-hydroxytryptamine 1D receptor HTR1D 0.0825
4757 Cytochrome P450 2C9 CYP2C9 0.0819
432 D(4) dopamine receptor DRD4 0.0818
885 5-hydroxytryptamine 1B receptor HTR1B 0.0795
716 5-hydroxytryptamine 7 receptor HTR7 0.071
6030 Cytochrome P450 2B6 CYP2B6 0.0682
163 D(1B) dopamine receptor DRD5 0.0644
617 Muscarinic acetylcholine receptor M2 CHRM2 0.0607
51 Muscarinic acetylcholine receptor M3 CHRM3 0.0565
274 Muscarinic acetylcholine receptor M5 CHRM5 0.0504
450 Muscarinic acetylcholine receptor M4 CHRM4 0.0491
4118 Cytochrome P450 3A5 CYP3A5 0.0489
789 Alpha-1D adrenergic receptor ADRA1D 0.0485
1181 Alpha-1-acid glycoprotein 1 ORM1 0.0445
6013 Cytochrome P450 2E1 CYP2E1 0.0418
6145 Solute carrier family 22 member 1 SLC22A1 0.0371
6107 Cytochrome P450 3A7 CYP3A7 0.0353
4924 Cytochrome P450 2C8 CYP2C8 0.0338
3923 Cholinesterase BCHE 0.0333
6144 Solute carrier family 22 member 2 SLC22A2 0.0332
474 Acetylcholinesterase ACHE 0.0332
1256 5-hydroxytryptamine 6 receptor HTR6 0.0332
6147 Solute carrier family 22 member 3 SLC22A3 0.0329
341 5-hydroxytryptamine 3 receptor HTR3A 0.0324
193 Beta-1 adrenergic receptor ADRB1 0.0312
5718 Cytochrome P450 2A6 CYP2A6 0.0312
766 Beta-2 adrenergic receptor ADRB2 0.0306
94 5-hydroxytryptamine 4 receptor HTR4 0.0304
982 Cocaine- and amphetamine-regulated transcript protein CARTPT 0.0299
118 Organic cation/carnitine transporter 2 SLC22A5 0.0273
401 Glutamate [NMDA] receptor subunit zeta-1 GRIN1 0.026
5251 Carbonyl reductase [NADPH] 1 CBR1 0.0255
6432 Transporter snf 0.0246
706 Glutamate [NMDA] receptor subunit 3A GRIN3A 0.0241
587 Serum albumin ALB 0.0237
1656 CYP2B protein CYP2B 0.0236
198 Sodium channel protein type 10 subunit alpha SCN10A 0.0219
1517 Beta-3 adrenergic receptor ADRB3 0.0217
696 Kappa-type opioid receptor OPRK1 0.0182
4120 NADPH--cytochrome P450 reductase POR 0.0179
174 Sigma 1-type opioid receptor SIGMAR1 0.0172
528 5-hydroxytryptamine 1E receptor HTR1E 0.0163
124 Histamine H2 receptor HRH2 0.0145
467 Delta-type opioid receptor OPRD1 0.0136
734 D1 dopamine receptor-interacting protein calcyon CALY 0.0134
904 Glutathione S-transferase P GSTP1 0.0127
776 Bile salt export pump ABCB11 0.0113
6024 Cytochrome P450 1A1 CYP1A1 0.0113
6106 Cytochrome P450 2C18 CYP2C18 0.0111
847 Mu-type opioid receptor OPRM1 0.0109
1757 Myeloperoxidase MPO 0.0103
362 Melatonin receptor type 1B MTNR1B 0.0103
571 Melatonin receptor type 1A MTNR1A 0.0103
5878 Alpha-7 nicotinic cholinergic receptor subunit CHRFAM7A 0.0099
872 Gamma-aminobutyric-acid receptor subunit alpha-1 GABRA1 0.0098
215 Sodium channel protein type 11 subunit alpha SCN11A 0.0096
101 Potassium voltage-gated channel subfamily H member 2 KCNH2 0.0094
750 Voltage-dependent calcium channel gamma-1 subunit CACNG1 0.0089
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0087
6182 Cytochrome P450 2J2 CYP2J2 0.0086
6176 UDP-glucuronosyltransferase 1-3 UGT1A3 0.0078
923 Glutamate receptor 3 GRIA3 0.0075
813 Neuronal acetylcholine receptor subunit alpha-2 CHRNA2 0.0075
458 Neuronal acetylcholine receptor subunit alpha-10 CHRNA10 0.0073
6025 UDP-glucuronosyltransferase 1-4 UGT1A4 0.0072
6099 Potassium voltage-gated channel subfamily D member 3 KCND3 0.0072
6098 Potassium voltage-gated channel subfamily D member 2 KCND2 0.0072
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.0072
6079 Neuronal acetylcholine receptor subunit alpha-3 CHRNA3 0.0065
220 Sodium channel protein type 5 subunit alpha SCN5A 0.0063
3876 Aromatic-L-amino-acid decarboxylase DDC 0.0061
6164 POU domain, class 5, transcription factor 1 POU5F1 0.006
6018 UDP-glucuronosyltransferase 1-9 UGT1A9 0.006
511 5-hydroxytryptamine 1F receptor HTR1F 0.0057
20 Prostaglandin G/H synthase 1 PTGS1 0.0056
833 Organic cation/carnitine transporter 1 SLC22A4 0.0056
6104 Dimethylaniline monooxygenase [N-oxide-forming] 1 FMO1 0.0051
1360 Sphingomyelin phosphodiesterase SMPD1 0.0049
921 Glutamate receptor 2 GRIA2 0.0047
6178 UDP-glucuronosyltransferase 2B7 UGT2B7 0.0046
6100 BDNF/NT-3 growth factors receptor NTRK2 0.0044
2981 Phospholipase A2, membrane associated PLA2G2A 0.0044
828 Phenylalanine-4-hydroxylase PAH 0.0043
3109 Phenylalanine-4-hydroxylase phhA 0.0043
3426 Glutamine synthetase glnA 0.0043
3987 Glutamine synthetase GLUL 0.0043
482 Glycine receptor subunit alpha-1 GLRA1 0.004
6086 Gamma-aminobutyric acid receptor subunit gamma-2 GABRG2 0.0036
4100 Gamma-aminobutyric-acid receptor subunit beta-2 GABRB2 0.0036
439 Glutamate [NMDA] receptor subunit epsilon-4 GRIN2D 0.0036
6101 Dimethylaniline monooxygenase [N-oxide-forming] 3 FMO3 0.0036
1618 High affinity nerve growth factor receptor NTRK1 0.0034
1086 Potassium voltage-gated channel subfamily KQT member 2 KCNQ2 0.0033
591 Glutamate [NMDA] receptor subunit 3B GRIN3B 0.0033
319 Opioid receptor, sigma 1 OPRS1 0.0031
858 Potassium voltage-gated channel subfamily A member 1 KCNA1 0.0026
153 Dopamine beta-hydroxylase DBH 0.0025
164 Histamine H4 receptor HRH4 0.0022
3810 Catechol O-methyltransferase COMT 0.002
6151 Monocarboxylate transporter 10 SLC16A10 0.0018
464 Glutamate [NMDA] receptor subunit epsilon-2 GRIN2B 0.0017
465 Calmodulin CALM1 0.0015
1898 Cytochrome P450 1B1 CYP1B1 0.0013
4114 Voltage-dependent L-type calcium channel subunit beta-3 CACNB3 0.001
4112 Voltage-dependent L-type calcium channel subunit beta-4 CACNB4 0.001
392 Voltage-dependent P/Q-type calcium channel subunit alpha-1A CACNA1A 0.001
4113 Voltage-dependent L-type calcium channel subunit alpha-1F CACNA1F 0.0009
3970 Voltage-dependent N-type calcium channel subunit alpha-1B CACNA1B 0.0009
15 Voltage-dependent T-type calcium channel subunit alpha-1I CACNA1I 0.0009
333 Voltage-dependent L-type calcium channel subunit beta-1 CACNB1 0.0009
781 ATP-sensitive inward rectifier potassium channel 11 KCNJ11 0.0009
535 Voltage-dependent T-type calcium channel subunit alpha-1G CACNA1G 0.0009
4110 Voltage-dependent L-type calcium channel subunit beta-2 CACNB2 0.0008
4115 Voltage-dependent L-type calcium channel subunit alpha-1D CACNA1D 0.0008
4111 Voltage-dependent L-type calcium channel subunit alpha-1S CACNA1S 0.0008
478 Voltage-dependent L-type calcium channel subunit alpha-1C CACNA1C 0.0008
6148 Multidrug resistance-associated protein 7 ABCC10 0.0007
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.0007
2164 Multidrug resistance-associated protein 4 ABCC4 0.0006
862 Multidrug resistance-associated protein 1 ABCC1 0.0006
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.0006
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0006
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