Chemistry:Para-Methoxymethamphetamine

From HandWiki
Short description: Stimulant and entactogen designer drug


PMMA
Clinical data
Other namesPMMA; p-Methoxymethamphetamine; para-Methoxy-N-methylamphetamine; 4-Methoxy-N-methylamphetamine; 4-MMA; Methyl-MA; 4-PMDA
Routes of
administration		Oral[1]
Drug classSerotonin–norepinephrine releasing agent; Monoamine oxidase inhibitor
Legal status
Legal status
Pharmacokinetic data
MetabolismCYP2D6, [1] [2]
MetabolitesPholedrine [3], para-methoxyamphetamine, 4-hydroxyamphetamine, 3,4-dihydroxymethamphetamine, oxilofrine [4] [5]
Onset of action≤1 hour[1]
Duration of action"Short"[1]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC11H17NO
Molar mass179.263 g·mol−1
3D model (JSmol)
  (verify)

para-Methoxymethamphetamine (PMMA), also known as 4-methoxy-N-methylamphetamine (4-MMA), is a serotonergic drug of the amphetamine family related to para-methoxyamphetamine (PMA).[1][2] It is the 4-methoxy analogue of methamphetamine.[1][2]

Little is known about the pharmacological properties, metabolism, and toxicity of PMMA; because of its structural similarity to PMA, which has known toxicity in humans, it is thought to have considerable potential to cause harmful side effects or death in overdose.[3] In the early 2010s, a number of deaths in users of the drug MDMA were linked to misrepresented tablets and capsules of PMMA.[4]

PMMA is a serotonin–norepinephrine releasing agent (SNRA)[5][6][7][8] as well as potent monoamine oxidase inhibitor (MAOI).[9] It has a reduced tendency to produce severe hyperthermia at low doses compared to PMA,[10][11] but at higher doses, side effects and risk of death become similar to those of PMA.[12]

The synthesis and effects of PMMA were described by American experimental chemist Alexander Shulgin in his book PiHKAL, where it is referred to by the name "methyl-MA", as the N-methylated form of 4-MA (PMA).[1]

Use and effects

According to Alexander Shulgin in his book PiHKAL (Phenethylamines I Have Known and Loved), the effects of PMMA at a dose of 110 mg orally included tachycardia, compulsive yawning, and nystagmus, among others.[1] It was said to have some of the physical side effects of the entactogen MDMA but none of its central effects.[1] No psychedelic-like effects were mentioned.[1]

Pharmacology

Pharmacodynamics

PMMA is a monoamine releasing agent (MRA).[5][6][7][8] The drug's EC50 values for induction of monoamine release in rat brain synaptosomes have been reported for the individual enantiomers of PMMA.[5][6][7] In the case of (S)-PMMA, they were 41 nM for serotonin, 147 nM for norepinephrine, and 1,000 nM for dopamine, whereas for (R)-PMMA, they were 134 nM for serotonin, >14,000 nM for norepinephrine, and 1,600 nM for dopamine.[5][6][7] Hence, PMMA appears to be a serotonin–norepinephrine releasing agent (SNRA) with weak effects on dopamine release.[5][6][7][8] The drug has been found to strongly release serotonin and to weakly release dopamine in the brain in rodents in vivo.[8]

In addition to its MRA activity, PMMA is a potent monoamine oxidase A (MAO-A) inhibitor.[9] Its IC50 for MAO-A inhibition has been reported to be 1,700 nM.[9] This is several-fold less potent than the related agents para-methoxyamphetamine (PMA) and 4-methylthioamphetamine (4-MTA).[9]

PMMA is said to lack affinity for the serotonin 5-HT2A receptor.[5] In one study, its affinities were >20,000 nM for the serotonin 5-HT1A receptor, 13,600 nM for the serotonin 5-HT2A receptor, and >13,000 nM for the serotonin 5-HT2C receptor.[13] On the other hand, PMMA shows much higher affinities for the mouse and rat trace amine-associated receptor 1 (TAAR1).[13]

In rodents, PMMA produces hyperlocomotion, no changes in locomotor activity, and/or catatonia, and has effects that are said to differ from those of amphetamine-like stimulants.[2][14][5] It has been said not to have amphetamine-like properties in rodents even at high doses.[2][14][5] Similarly, PMMA did not substitute for the psychedelic DOM.[14] On the other hand, in contrast to PMA, PMMA fully substituted for MDMA in drug discrimination tests in rodents, despite not having MDMA-like psychoactive effects in humans.[2][5][1] In any case, PMMA is said to lack the amphetamine- or stimulant-like properties of MDMA.[14][5]

Monoamine release of PMMA and related agents (EC50, nM)
Compound 5-HT NE DA Ref
d-Amphetamine 698–1,765 6.6–7.2 5.8–24.8 [15][16]
d-Methamphetamine 736–1,292 12.3–13.8 8.5–24.5 [15][17]
2-Methoxyamphetamine ND 473 1,478 [18]
3-Methoxyamphetamine ND 58.0 103 [18]
para-Methoxyamphetamine (PMA) ND 166 867 [18][7]
PMMA ND ND ND ND
  (S)-PMMA 41 147 1,000 [5][6][7]
  (R)-PMMA 134 >14,000 1,600 [5][6][7]
4-Methylamphetamine (4-MA) 53.4 22.2 44.1 [19][20][18]
4-Methylmethamphetamine (4-MMA) 67.4 66.9 41.3 [21][22]
para-Chloroamphetamine (PCA) 28.3 23.5–26.2 42.2–68.5 [20][18][23][24]
para-Chloromethamphetamine (PCMA) 29.9 36.5 54.7 [23][24]
Methedrone (4-MeO-MC) 120–195 111 506–881 [25][26][27][28][29]
Mephedrone (4-MMC) 118.3–122 58–62.7 49.1–51 [17][16][26][28][29]
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: [30][31]

Chemistry

Synthesis

The chemical synthesis of PMMA has been described.[1]

Detection

Analogues

Analogues of PMMA include para-methoxyamphetamine (PMA), para-methoxy-N-ethylamphetamine (PMEA), 4-methylthio-N-methylamphetamine (4-MTMA), 4-methyl-N-methylamphetamine (4-MMA; mephedrine), para-chloro-N-methylamphetamine (PCMA), 4-fluoro-N-methylamphetamine (4-FMA), methoxyphenamine (2-methoxy-N-methylamphetamine; OMMA), 3-methoxy-N-methylamphetamine (MMMA), and methedrone (4-methoxymethcathinone; bk-PMMA), among others.[1][2]

History

PMMA was first described in the scientific literature by at least 1984.[32]

Society and culture

Recreational use

Tablets of PMMA recovered by the U.S. Drug Enforcement Administration

PMMA has been found in tablets and capsules of the MDMA sold as "ecstasy". A number of deaths have been attributed to tablets sold as ecstasy that contained other substances, such as PMMA's structural analog, PMA.[33][34] Death can occur when an ecstasy user believes they are consuming recreational doses of MDMA, when they are in fact consuming a lethal dose of another substance with similar effects. PMA is of particular concern because it not only causes a release of serotonin but also acts as a monoamine oxidase inhibitor (MAOI); if it is used in combination with MDMA or another MDMA-like substance, serotonin syndrome can result.[35]

Deaths

In January 2011, the Norwegian Broadcasting Corporation reported that Norway had seen 12 deaths related to PMMA over the course of six months. In March 2011, Dutch media reported that there had been four deaths in the province of Limburg since November 2010.[36] In April 2011, Icelandic media reported the death of a young woman that may have been connected to PMMA. In 2011, four deaths were recorded in Scotland as a result of ecstasy tablets which also contained PMMA.[37]

In January 2012, a number of ecstasy-related deaths in Canada in the previous year were linked to PMMA overdoses. In the single year, approximately 45 exposures occurred, resulting in 21 deaths. Cases were centred primarily in Calgary and Vancouver.[38][39][40][41][42][43]

In September 2012, the deaths of two men in County Cork, Ireland, have been linked to PMMA overdoses.[44] In the same month, the death of a man in Queensland, Australia was attributed to PMMA.[45]

In June 2013 a PMMA-related death occurred in the Dutch city of 's-Hertogenbosch.[46] Two months later, In August 2013, another possibly PMMA-related death occurred in the nearby town of Sliedrecht.[47][48][49]

In January 2015 in the UK four people died, suspected of taking ecstasy containing PMMA.[50] In the same month, in Sweden, another man died from ecstasy laced with PMMA.[51]

In May 2015 a young woman died in Dublin, Ireland, after taking what is suspected to be PMMA.[52]

In April 2016 four young Argentines and one Uruguayan died during a massive rave called "Time Warp" in Buenos Aires and five more were hospitalized. PMMA was found in their bodies. [53]

United Kingdom

United States

On June 25, 2021, the DEA finalized a rule placing PMMA on the Controlled Substance Act federal Schedule as a Schedule I substance effective July 26, 2021.[54]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 Shulgin, Alexander; Shulgin, Ann (September 1991). PiHKAL: A Chemical Love Story. Berkeley, California: Transform Press. ISBN 0-9630096-0-5. OCLC 25627628. http://www.erowid.org/library/books_online/pihkal/pihkal.shtml. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. 1. Berkeley: Transform Press. 2011. ISBN 978-0-9630096-3-0. https://books.google.com/books?id=68-huAAACAAJ. Retrieved 2 November 2024. 
  3. ↑ "A fatal paramethoxymethamphetamine intoxication". Legal Medicine. 5 5 (Suppl 1): S138-41. March 2003. doi:10.1016/s1344-6223(02)00096-2. PMID 12935573. 
  4. ↑ "Five B.C. deaths linked to lethal chemical PMMA". vancouversun. Vancouver Sun. 10 January 2012. https://vancouversun.com/news/five-bc-deaths-linked-to-lethal-chemical-pmma. 
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 "The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse". J Med Chem 60 (7): 2605–2628. April 2017. doi:10.1021/acs.jmedchem.7b00085. PMID 28244748. "Table 5. Action of MDMA, MDA, and PMMA as Releasing Agents at the Serotonin (SERT), Dopamine (DAT), and Norepinephrine (NET) Transporters18,59,60 [...] a Data, although from different publications, were obtained from the same laboratory.". 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 "Drug Discrimination and Mechanisms of Drug Action". Drug Discrimination. Wiley. 5 August 2011. pp. 183–216. doi:10.1002/9781118023150.ch6. ISBN 978-0-470-43352-2. "PMMA is a 5-HT releasing agent. S(+)PMMA is a potent releaser of 5-HT (EC50 = 41 nM) and NE (EC50 = 147 nM) with reduced activity as a releaser of DA (EC50 = 1,000 nM); the R(−)isomer of PMMA is a releaser of 5-HT (EC50 = 134 nM) with reduced potency for release of NE (EC50 = 1,600 nM) and DA (EC50 > 14,000 nM) (R.B. Rothman, unpublished data)." 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Vekariya R (2012). Towards Understanding the Mechanism of Action of Abused Cathinones (Master of Science thesis). Virginia Commonwealth University. doi:10.25772/AR93-7024 – via VCU Theses and Dissertations.
  8. ↑ 8.0 8.1 8.2 8.3 "5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: a comparative study using in vivo microdialysis". Eur Neuropsychopharmacol 24 (8): 1362–1370. August 2014. doi:10.1016/j.euroneuro.2014.04.009. PMID 24862256. 
  9. ↑ 9.0 9.1 9.2 9.3 "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol 10. 2019. doi:10.3389/fphar.2019.01590. PMID 32038257. 
  10. ↑ "Initial characterization of PMMA as a discriminative stimulus". Pharmacology, Biochemistry, and Behavior 57 (1–2): 151–8. 1997. doi:10.1016/S0091-3057(96)00306-1. PMID 9164566. 
  11. ↑ "PMMA-stimulus generalization to the optical isomers of MBDB and 3,4-DMA". Pharmacology, Biochemistry, and Behavior 69 (1–2): 261–7. 2001. doi:10.1016/S0091-3057(01)00530-5. PMID 11420094. 
  12. ↑ "Three fatal cases of PMA and PMMA poisoning in Denmark". Journal of Analytical Toxicology 27 (4): 253–6. 2003. doi:10.1093/jat/27.4.253. PMID 12820749. 
  13. ↑ 13.0 13.1 "Monoamine transporter and receptor interaction profiles of a new series of designer cathinones". Neuropharmacology 79: 152–160. April 2014. doi:10.1016/j.neuropharm.2013.11.008. PMID 24275046. 
  14. ↑ 14.0 14.1 14.2 14.3 "Arylalkylamine drugs of abuse: an overview of drug discrimination studies". Pharmacol Biochem Behav 64 (2): 251–256. October 1999. doi:10.1016/s0091-3057(99)00045-3. PMID 10515299. 
  15. ↑ 15.0 15.1 "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse 39 (1): 32–41. January 2001. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. 
  16. ↑ 16.0 16.1 "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology 38 (4): 552–562. 2013. doi:10.1038/npp.2012.204. PMID 23072836. 
  17. ↑ 17.0 17.1 "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology 37 (5): 1192–1203. 2012. doi:10.1038/npp.2011.304. PMID 22169943. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. July 2008. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf. 
  19. ↑ "Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs". The Journal of Pharmacology and Experimental Therapeutics 313 (2): 848–854. May 2005. doi:10.1124/jpet.104.080101. PMID 15677348. 
  20. ↑ 20.0 20.1 Forsyth AN (22 May 2012). Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines (Ph.D. thesis). University of New Orleans. Retrieved 4 November 2024 – via ScholarWorks@UNO.
  21. ↑ "N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability". Neuropsychopharmacology 42 (10): 1950–1961. September 2017. doi:10.1038/npp.2017.98. PMID 28530234. 
  22. ↑ Sakloth F (11 December 2015). Psychoactive synthetic cathinones (or 'bath salts'): Investigation of mechanisms of action. Theses and Dissertations (Ph.D. thesis). Virginia Commonwealth University. doi:10.25772/AY8R-PW77. Retrieved 24 November 2024 – via VCU Scholars Compass.
  23. ↑ 23.0 23.1 "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology 245. March 2024. doi:10.1016/j.neuropharm.2023.109827. PMID 38154512. 
  24. ↑ 24.0 24.1 Nicole L (2022). In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones (Ph.D. thesis). University of Arkansas for Medical Sciences. ProQuest 2711781450. Retrieved 5 December 2024. FIGURE 2-6: Release: Effects of the specified test drug on monoamine release by DAT (red circles), NET (blue squares), and SERT (black traingles) in rat brain tissue. [...] EC50 values determined for the drug indicated within the panel. [...]
  25. ↑ "Neuropharmacology of Synthetic Cathinones". Handb Exp Pharmacol. Handbook of Experimental Pharmacology 252: 113–142. 2018. doi:10.1007/164_2018_178. ISBN 978-3-030-10560-0. PMID 30406443. 
  26. ↑ 26.0 26.1 "The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes". Psychopharmacology 236 (3): 915–924. March 2019. doi:10.1007/s00213-018-5063-9. PMID 30341459. 
  27. ↑ Shalabi AR (14 December 2017). Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters. Theses and Dissertations (Ph.D. thesis). Virginia Commonwealth University. doi:10.25772/M4E1-3549. Retrieved 24 November 2024 – via VCU Scholars Compass.
  28. ↑ 28.0 28.1 "Systematic Structure-Activity Studies on Selected 2-, 3-, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents". ACS Chem Neurosci 10 (1): 740–745. January 2019. doi:10.1021/acschemneuro.8b00524. PMID 30354055. 
  29. ↑ 29.0 29.1 "Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues". Br J Pharmacol 172 (10): 2433–2444. May 2015. doi:10.1111/bph.13030. PMID 25438806. 
  30. ↑ "Monoamine transporters and psychostimulant drugs". Eur J Pharmacol 479 (1–3): 23–40. October 2003. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135. 
  31. ↑ "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. https://zenodo.org/record/1235860. 
  32. ↑ Clark, Cc (1 October 1984). "The Identification of Methoxy- N -Methylamphetamines". Journal of Forensic Sciences 29 (4): 1056–1071. doi:10.1520/JFS11772J. ISSN 0022-1198. https://dl.astm.org/jofs/article/29/4/1056/8311/The-Identification-of-Methoxy-N-Methylamphetamines. Retrieved 26 February 2026. 
  33. ↑ "Paramethoxyamphetamine (PMA) poisoning; a 'party drug' with lethal effects". Acta Anaesthesiologica Scandinavica 47 (10): 1298–9. November 2003. doi:10.1046/j.1399-6576.2003.00245.x. PMID 14616331. 
  34. ↑ "Fatal paramethoxy-amphetamine (PMA) poisoning in the Australian Capital Territory". The Medical Journal of Australia 188 (7): 426. April 2008. doi:10.5694/j.1326-5377.2008.tb01695.x. PMID 18393753. 
  35. ↑ "p-Methoxyamphetamine, a potent reversible inhibitor of type-A monoamine oxidase in vitro and in vivo". The Journal of Pharmacy and Pharmacology 32 (4): 262–6. April 1980. doi:10.1111/j.2042-7158.1980.tb12909.x. PMID 6103055. 
  36. ↑ "PMMA deaths in Holland". nu.nl. https://translate.google.com/translate?js=n&prev=_t&hl=en&ie=UTF-8&layout=2&eotf=1&sl=nl&tl=en&u=http%3A%2F%2Fwww.nu.nl%2Fbinnenland%2F2535695%2Fpinkpopgangers-moeten-uitkijken-met-xtc.html. 
  37. ↑ "Warning over ecstasy pills that raise overdose risk". BBC News. 16 December 2011. https://www.bbc.co.uk/news/uk-scotland-16224849. 
  38. ↑ "Rare chemical found in fatal ecstasy". The Province. 15 January 2012. https://theprovince.com/life/Rare+chemical+found+fatal+ecstasy/5998482/story.html. 
  39. ↑ "Overdose death investigated". Nanton News. 24 January 2012. http://www.nantonnews.com/ArticleDisplay.aspx?e=3446181. 
  40. ↑ "Seized substances sent for testing after suspected overdose". Calgary Herald. https://calgaryherald.com/news/alberta/Update+Seized+substances+sent+testing+after+suspected+overdose+SAIT/6037966/story.html. 
  41. ↑ "Tainted ecstasy linked to five Calgary deaths could be from B.C.". Vancouver Sun. 12 January 2012. https://vancouversun.com/touch/story.html?id=5980841. 
  42. ↑ "Authorities renew warning about street drugs". The City of Calgary Newsroom. http://newsroom.calgary.ca/pr/calgary/authorities-renew-warning-about-221684.aspx. 
  43. ↑ "Ecstasy laced with meth in overdose cases". https://www.cbc.ca/news/canada/calgary/ecstasy-laced-with-meth-blamed-in-5-calgary-deaths-1.1162942. 
  44. ↑ "Dangerous drug linked to Kinsale deaths". Irish Independent. 13 September 2012. http://www.irishtimes.com/newspaper/ireland/2012/0913/1224323959421.html. 
  45. ↑ "Queensland Police investigate three deaths linked to 'poison pill' ecstasy overdoses". news.com.au. 9 September 2012. http://www.news.com.au/national/queensland-police-investigate-three-deaths-linked-to-poison-pill-ecstasy-overdoses/story-fndo4ckr-1226468070006. 
  46. ↑ "Den Bosch issues a warning for dangerous XTC-pills". nu.nl. https://translate.google.com/translate?js=n&prev=_t&hl=en&ie=UTF-8&layout=2&eotf=1&sl=nl&tl=en&u=http%3A%2F%2Fwww.nu.nl%2Fbinnenland%2F3498768%2Fbosch-waarschuwt-gevaarlijke-xtc-pillen.html. 
  47. ↑ "Tiener overleden aan drugs". http://www.hetkompassliedrecht.nl/lokaal/tiener_overleden_aan_drugssliedrecht__in_sliedrecht_is_zondag_een_meisje_van_zestien_jaar_overleden_2526291.html. 
  48. ↑ "Naomi (16): dood door roze xtc-pil". 26 August 2013. http://www.misdaadjournalist.nl/2013/08/naomi-16-dood-door-roze-xtc-pil/. 
  49. ↑ "Waarschuwing: dodelijke 'XTC' in omloop". http://www.camilleri.nl/2013/08/waarschuwing-dodelijke-xtc-in-omloop/. 
  50. ↑ "Man charged after ecstasy deaths". BBC News. 15 May 2018. https://www.bbc.co.uk/news/uk-england-30671300. 
  51. ↑ "Varning för livsfarlig ecstasy" (in Swedish). 2 January 2015. http://www.aftonbladet.se/nyheter/article20103807.ab. 
  52. ↑ "Dublin student dies after taking PMMA tablets in nightclub". 17 May 2015. http://www.irishexaminer.com/breakingnews/ireland/dublin-student-dies-after-taking-pmma-tablets-in-nightclub-677531.html. 
  53. ↑ "Conmoción por la muerte de cinco jóvenes en una fiesta electrónica" (in Spanish). La Nación. 17 April 2016. http://www.lanacion.com.ar/1890177-conmocion-por-la-muerte-de-cinco-jovenes-en-una-fiesta-electronica. 
  54. ↑ "Schedules of Controlled Substances: Placement of para-Methoxymethamphetamine (PMMA) in Schedule I". June 25, 2021. https://www.federalregister.gov/documents/2021/06/25/2021-13460/schedules-of-controlled-substances-placement-of-para-methoxymethamphetamine-pmma-in-schedule-i. 

Template:TAAR modulators



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Para-Methoxymethamphetamine&oldid=4308943"