4,4'-Dimethylaminorex

Last updated
4,4'-Dimethylaminorex
4,4'-Dimethylaminorex.svg
Clinical data
Other names4,4'-DMAR
ATC code
  • none
Legal status
Legal status
  • BR: Class F2 (Prohibited psychotropics) [1]
  • DE: Anlage II (Authorized trade only, not prescriptible)
  • UK: Class A
  • US:Schedule I [2]
  • Illegal in Czech Republic and Sweden
Identifiers
  • 4-Methyl-5-(4-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
Formula C11H14N2O
Molar mass 190.246 g·mol−1
3D model (JSmol)
  • CC(N=C(N)O1)C1C2=CC=C(C)C=C2
  • InChI=1S/C11H14N2O/c1-7-3-5-9(6-4-7)10-8(2)13-11(12)14-10/h3-6,8,10H,1-2H3,(H2,12,13)
  • Key:NPILLHMQNMXXTL-UHFFFAOYSA-N

4,4'-Dimethylaminorex (abbreviated as 4,4'-DMAR), sometimes referred to by the street name "Serotoni", is a psychostimulant and entactogen designer drug related to aminorex, 4-methylaminorex, and pemoline. [3] It was first detected in the Netherlands in December 2012, [4] and has been sold as a designer drug around Europe since mid-2013.

Contents

4,4'-DMAR had been linked to at least 31 deaths in Hungary, Poland, and the UK by February 2014, mostly when consumed in combination with other drugs. [5] Nineteen deaths linked to 4,4'-DMAR were reported in Northern Ireland in the same time period. [6]

Pharmacology

Pharmacodynamics

4,4'-DMAR is a monoamine releasing agent (MRA) and acts specifically as a highly potent and well-balanced serotonin-norepinephrine-dopamine releasing agent (SNDRA), with EC50 values for serotonin, norepinephrine, and dopamine release of 18.5 nM, 26.9 nM, and 8.6 nM, respectively. [3] [7] It also interacts with the vesicular monoamine transporter 2 (VMAT2) with similar potency as MDMA. [7] [8]

Monoamine release of 4,4'-DMAR and related agents (EC50 Tooltip Half maximal effective concentration, nM)
Compound NE Tooltip Norepinephrine DA Tooltip Dopamine 5-HT Tooltip SerotoninRef
Phenethylamine 10.939.5>10,000 [9] [10] [11]
Dextroamphetamine 6.6–10.25.8–24.8698–1,765 [12] [13] [11] [14]
Dextromethamphetamine 12.3–14.38.5–40.4736–1,292 [12] [15] [11] [14]
Aminorex 15.1–26.49.1–49.4193–414 [12] [16] [11] [7] [14]
cis-4-MAR 4.81.753.2 [7] [16]
cis-4,4'-DMAR 11.8–31.68.6–24.417.7–59.9 [16] [17] [7]
trans-4,4'-DMAR 31.624.459.9 [17] [7]
cis-MDMAR 14.810.243.9 [17]
trans-MDMAR 38.936.273.4 [17]
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: [18] [19]

In contrast to many other MRAs, 4,4'-DMAR is inactive as a trace amine-associated receptor 1 (TAAR1) agonist. [7] As a result, whereas many other MRAs may auto-inhibit and constrain their effects via TAAR1 agonism, this may not occur with 4,4'-DMAR. [7] The drug also shows very weak interactions with the serotonin 5-HT2A and 5-HT2C receptors, though appears to be inactive at the serotonin 5-HT2B receptor. [7] [8]

Legality

The UK Home Office expressed intent to ban 4,4'-DMAR following advice from the Advisory Council on the Misuse of Drugs [20] and subsequently it became a class A drug on 11 March 2015. [21]

4,4'-DMAR is an Anlage II controlled substance in Germany as of May 2015. [22]

Sweden's public health agency suggested to classify 4,4'-DMAR as hazardous substance on November 10, 2014. [23]

4,4'-DMAR is also banned in the Czech Republic. [24]

4,4'-DMAR is a Schedule I controlled substance in the US as of November 8, 2021. It only received two public comments during its public commenting period prior to being scheduled. [25] [26]

See also

Related Research Articles

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<span class="mw-page-title-main">4-Methylaminorex</span> Group of stereoisomers

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<span class="mw-page-title-main">Dopamine releasing agent</span> Type of drug

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<span class="mw-page-title-main">Substituted cathinone</span> Class of chemical compounds

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References

  1. ↑ Anvisa (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  2. ↑ "2021 - Placement of 4,4'-DMAR in Schedule I". www.deadiversion.usdoj.gov. Retrieved 2021-10-14.
  3. 1 2 Brandt SD, Baumann MH, Partilla JS, Kavanagh PV, Power JD, Talbot B, et al. (2014). "Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni')". Drug Testing and Analysis. 6 (7–8): 684–95. doi:10.1002/dta.1668. PMC   4128571 . PMID   24841869.
  4. ↑ "EMCDDA 2012 Annual report on the state of the drugs problem in Europe" (PDF). Archived (PDF) from the original on 2014-04-23. Retrieved 2014-04-21.
  5. ↑ "Risk Assessment Report of a new psychoactive substance: 4-methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-amine (4,4′-dimethylaminorex, 4,4′-DMAR)" (PDF). European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). November 2014. Archived (PDF) from the original on 2016-03-16. Retrieved 2016-02-11.
  6. ↑ "Unregulated stimulant drug blamed for 19 deaths, Belfast inquest told". The Guardian. 5 June 2014. Archived from the original on 8 February 2017. Retrieved 13 December 2016.
  7. 1 2 3 4 5 6 7 8 9 Maier J, Mayer FP, Brandt SD, Sitte HH (October 2018). "DARK Classics in Chemical Neuroscience: Aminorex Analogues". ACS Chem Neurosci. 9 (10): 2484–2502. doi:10.1021/acschemneuro.8b00415. PMC   6287711 . PMID   30269490. It has recently been shown that 4,4'-DMAR binds to monoamine transporters with higher affinities compared to monoamine receptors, albeit it has also been shown to bind to hDAT, hNET, hSERT and 5-HT2A and 5-HT2C receptors with relatively low affinities135 (see Table 1). Due to the lack of interaction with the trace amine-associated receptor 1 (TAAR1), 4,4'- DMAR is suspected to be unable to trigger the auto-inhibitory pathway that, for example, MDMA possesses at least in rodents135,183,184. [...] It has recently been shown that 4,4′-DMAR inhibits the vesicular monoamine transporter 2 (VMAT2; SLC18A2) with a potency similar to that of MDMA.135 Perturbed function of VMAT2 has been associated with neurotoxicity.224,225 [...] As mentioned before, in contrast to other amphetamine-type stimulants, 4,4′-DMAR does not interact with rat and mouse TAAR1 and therefore lacks the autoinhibitory pathway that attenuates monoamine release and mediates the neuroprotective effects.231,232 It has however been shown that many psychoactive compounds stimulate human TAAR1 less potently than the receptor's rodent counterparts.184 [...] While it has been shown that 4,4′-DMAR binds to the 5-HT2A and 5-HT2C receptors,135 receptor binding assays for 5-HT2B have not been conducted yet.
  8. 1 2 Maier J, Mayer FP, Luethi D, Holy M, Jäntsch K, Reither H, Hirtler L, Hoener MC, Liechti ME, Pifl C, Brandt SD, Sitte HH (August 2018). "The psychostimulant (±)-cis-4,4'-dimethylaminorex (4,4'-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters". Neuropharmacology. 138: 282–291. doi:10.1016/j.neuropharm.2018.06.018. PMID   29908239.
  9. ↑ Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC   4297708 . PMID   25548026.
  10. ↑ Forsyth, Andrea N (22 May 2012). "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO. Retrieved 4 November 2024.
  11. 1 2 3 4 Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN   978-0-470-11790-3. OCLC   181862653. OL   18589888W.
  12. 1 2 3 Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID   11071707. S2CID   15573624.
  13. ↑ Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW (March 2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC   3572453 . PMID   23072836.
  14. 1 2 3 Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB (1999). "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc (PDF). NIDA Res Monogr. Vol. 180. pp. 1–476 (252). PMID   11680410. RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays.
  15. ↑ Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (April 2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC   3306880 . PMID   22169943.
  16. 1 2 3 Brandt SD, Baumann MH, Partilla JS, Kavanagh PV, Power JD, Talbot B, Twamley B, Mahony O, O'Brien J, Elliott SP, Archer RP, Patrick J, Singh K, Dempster NM, Cosbey SH (2014). "Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni')". Drug Testing and Analysis. 6 (7–8): 684–695. doi:10.1002/dta.1668. PMC   4128571 . PMID   24841869.
  17. 1 2 3 4 McLaughlin G, Morris N, Kavanagh PV, Power JD, Twamley B, O'Brien J, Talbot B, Dowling G, Mahony O, Brandt SD, Patrick J, Archer RP, Partilla JS, Baumann MH (July 2015). "Synthesis, characterization, and monoamine transporter activity of the new psychoactive substance 3',4'-methylenedioxy-4-methylaminorex (MDMAR)". Drug Testing and Analysis. 7 (7): 555–564. doi:10.1002/dta.1732. PMC   5331736 . PMID   25331619.
  18. ↑ Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID   14612135.
  19. ↑ Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Curr Top Med Chem. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID   17017961.
  20. ↑ "Letter to ACMD regarding advice on MT-45 and 4,4'-DMAR". UK Home Office. 26 November 2014. Archived from the original on 19 February 2015. Retrieved 19 February 2015.
  21. ↑ "Circular 003/2015: a change to the Misuse of Drugs Act 1971: control of MT-45 and 4,4'-DMAR". UK Home Office. 20 February 2015. Archived from the original on 2 April 2015. Retrieved 11 March 2015.
  22. ↑ "Gesetz über den Verkehr mit Betäubungsmitteln (Betäubungsmittelgesetz - BtMG) Anlage II (zu § 1 Abs. 1) (verkehrsfähige, aber nicht verschreibungsfähige Betäubungsmittel)" (in German). Archived from the original on 24 September 2015. Retrieved 29 June 2015.
  23. ↑ "Cannabinoider föreslås bli klassade som hälsofarlig vara" (in Swedish). Retrieved 29 June 2015.
  24. ↑ "Látky, o které byl doplněn seznam č. 4 psychotropních látek (příloha č. 4 k nařízení vlády č. 463/2013 Sb.)" (PDF) (in Czech). Ministerstvo zdravotnictví. Archived (PDF) from the original on 2016-03-09. Retrieved 2016-02-06.
  25. ↑ "Federal Register :: Request Access".
  26. ↑ "2021 - Placement of 4,4'-DMAR in Schedule I".
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