Chemistry:4-Methylaminorex

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4-Methylaminorex (4-MAR, 4-MAX) is a stimulant drug of the 2-amino-5-aryloxazoline group that was first synthesized in 1960 by McNeil Laboratories.[1] It is also known by its street name "U4Euh" ("Euphoria"). It is banned in many countries as a stimulant. 4-Methylaminorex has effects comparable to methamphetamine but with a longer duration.

Chemistry

4-Methylaminorex exists as four stereoisomers : (±)-cis and (±)-trans. The (±)-cis isomers are the form used recreationally.

Synthesis

The (±)-cis isomers [racemate (1:1-mixture) of the (4R,5S)-isomer and the enantiomeric (4S,5R)-isomer] generally synthesized from dl-phenylpropanolamine in one step by cyclization with cyanogen bromide (sometimes prepared in situ by reacting sodium cyanide with bromine).[2][3]

Alternate synthesis routes generally involve more steps, such as replacing cyanogen bromide with sodium or potassium cyanate to form an intermediate and then reacting it with concentrated hydrochloric acid. A method reported in microgram replaced the need for a separate addition of hydrochloric acid by starting with the hydrochloride salt of the dl-phenylpropanolamine but side-products are noted.[2]

The (±)-trans isomers [racemate (1:1-mixture) of the (4S,5S)-isomer and the enantiomeric (4R,5R)-isomer] are synthesized in the same manner above but dl-norephedrine is used as the starting material instead. The cyanate reaction proceeds differently from the cyanogen bromide and transforms norephedrine into trans-4-methylaminorex instead, as noted in the DEA micrograph. The cyanogen bromide, by comparison, transformed norephedrine into the cis isomer and norpseudoephedrine into the trans isomers of the final product.[2]

Dosage

4-Methylaminorex can be smoked, insufflated or taken orally.

As an anorectic, the ED50 is 8.8 mg/kg in rats for the (±)-cis isomers. The (±)-trans isomers are slightly more potent at 7.0 mg/kg. As a recreational drug, the effective dosage ranges from 5 to 25 mg.[4]

In the 1970s McNeil Laboratories, Inc. was trying to bring 4-methylaminorex to drug market as a sympathomimetic (most commonly used as asthma-medicines), research name was McN-822, they mention that human dose would have been 0.25 mg/kg of body weight. They mention also LD50: 17 mg/kg p.o for mice[5]

There is a patent about the use of 4-methylaminorex "as a nasal decongestant which, when administered orally, does not produce adverse central nervous system stimulant effects as experienced with other decongestants and anorexiants." Dose mentioned is 0.25 mg/kg of body weight.[6]

Effects

4-methylaminorex produces long-lasting effects, generally up to 16 hours in duration if taken orally and up to 12 hours if smoked or insufflated. Large doses have been reported anecdotally to last up to 36 hours. The effects are stimulant in nature, producing euphoria, increased attention, and increased cognition. Anecdotally, it has been reported to produce effects similar to nootropics. However, there is no research to support the claim that it is different or more effective than other psychostimulants in this respect. Moreover, 4-methylaminorex does not have the established safety profile of widely used clinical psychostimulants such as methylphenidate and dextroamphetamine.

Time (h) Urinary levels (μg/ml)
0-6 45
6-24 1.0
24-36 0.1
36-48 not detected

There has been one reported death due to 4-methylaminorex and diazepam‍—‍‌concentrations of 4-methylaminorex were 21.3 mg/L in blood and 12.3 mg/L in urine. Diazepam concentration in blood was 0.8 mg/L.[7] One experiment on rats has studied excretion of 4-methylaminorex in urine: "The concentration of trans-4-methylaminorex in rat urine following four injections of the trans-4S,5S isomer 5 mg/kg i.p each, at intervals of 12 h in 2 days, as measured quantitatively by GC/MS".[8]

Another study focused on pharmacokinetics and tissue distribution of the stereoisomers of 4-methylaminorex in rats.[9]

"Pulmonary hypertension has been associated with ingestion of the appetite suppressant aminorex. A similar compound, 4-methylaminorex, was discovered on the property of three individuals with diagnoses of pulmonary hypertension."[10]

Neurotoxicity studies

There have been three studies studying possible neurotoxicity of 4-methylaminorex. First study[11] using quite high doses (highest dose caused clonic seizures and some rats died) in rats and studying short-term effects (rats were killed 30 min to 18 h after injection of 5, 10 or 20 mg/kg of racemic cis-4-methylaminorex) suggested reduction in tryptophan hydroxylase (TPH) activity (a possible marker for serotonin neurotoxicity) but citing study: "No change in TPH activity was observed 30 min after injection; by 8 h the activity of this enzyme appeared to be recovering." and "this agent is significantly less neurotoxic than methamphetamine or MDMA."

A study[12] published 2 years later than first one also suggested reduction in tryptophan hydroxylase activity, they used quite high dose too (10 mg/kg of cis-4-methylaminorex) and studied also long-term effects (rats were killed 3 h, 18 h or 7 days after injection), they found reduction of 20-40% of tryptophan hydroxylase (TPH) activity and "recovery of TPH activity occurred 18 h after treatment, but was significantly decreased again by 7 days." but "It is noteworthy that, unlike the other analogs, the striatal levels of 5-HT did not decline with TPH activity following multiple 4-methylaminorex treatment"

The latest study[13] (using mice) was not able to find any long-term effects suggesting neurotoxicity and instead found an increase in serotonin levels, they also used high doses (15 mg/kg of each isomers studied) "The dosages used in the present experiments are about 6-10 times than the effective doses of aminorex and stereoisomers inhibition of food intake." Doses were repeated 3 times a day and mice were killed 7 days after last dose. "Since a long-lasting depletion of dopamine or 5-HT appears to be a good predictor of dopamine or 5-HT neurotoxicity (Wagner et al. 1980; Ricaurte et al. 1985), the results suggest that the aminorex compounds except 4S,5S-dimethylaminorex, unlike MDMA or fenfluramine, are not toxic to either dopamine or 5-HT neurotransmitter systems in the CBA strain of mice. It was reported that although multiple doses of 4-methylaminorex caused long-term, i.e., seven-day, declines in striatal tryptophan hydroxylase activity in SD rats, no changes were found in 5-HT and 5-HIAA levels (Hanson et al. 1992).[10]

That first study [11] also suggested reduced dopamine (DA) levels (a possible marker for dopamine neurotoxicity), but citing study: "However, 8 h after drug administration no differences from control values were seen in DA, DOPAC or HVA levels." and again later studies [12-13] didn't find any long-term reduction.

Pharmacology

Monoamine release of 4-MAR and related agents (EC50, nM)
Compound NE DA 5-HT Ref
Phenethylamine 10.9 39.5 >10,000 [14][15][16]
Dextroamphetamine 6.6–10.2 5.8–24.8 698–1,765 [17][18][16][19]
Dextromethamphetamine 12.3–14.3 8.5–40.4 736–1,292 [17][20][16][19]
Aminorex 15.1–26.4 9.1–49.4 193–414 [17][21][16][22][19]
cis-4-MAR 4.8 1.7 53.2 [22][21]
cis-4,4'-DMAR 11.8–31.6 8.6–24.4 17.7–59.9 [21][23][22]
trans-4,4'-DMAR 31.6 24.4 59.9 [23][22]
cis-MDMAR 14.8 10.2 43.9 [23]
trans-MDMAR 38.9 36.2 73.4 [23]
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:[24][25]

4-MAR acts as a highly potent monoamine releasing agent (MRA).[22][21] It is specifically a norepinephrine–dopamine releasing agent (NDRA) with weak effects on serotonin.[21][22] The drug's EC50 values for induction of monoamine neurotransmitter release have been found to be 4.8 nM for norepinephrine, 1.7 nM for dopamine, and 53.2 nM for serotonin.[21] It is among the most potent and selective dopamine releasing agents (DRAs) known.[21][24][25][16]

In contrast to many other MRAs, 4-MAR is inactive at the mouse and rat trace amine-associated receptor 1 (TAAR1).[26] Similarly, 4,4'-dimethylaminorex (4,4'-DMAR) is inactive at the mouse and rat TAAR1.[26][22][27] Many other monoamine releasing agents (MRAs), such as many amphetamines, are rodent and/or human TAAR1 agonists.[28][29] Activation of the TAAR1 may auto-inhibit and thereby constrain the monoaminergic effects of these agents.[22][27][26] Lack of TAAR1 agonism in the case of aminorex analogues might enhance their effects relative to MRAs possessing TAAR1 agonism.[22][27][26]

Misuse potential

The results of animal experiments conducted with this drug suggest that it has an abuse liability similar to cocaine and amphetamine. One study found that, "stimulus properties of racemic cis, racemic trans, and all four individual optical isomers of 4-methylaminorex were examined in rats trained to discriminate 1 mg/kg of S(+)amphetamine sulfate from saline. The S(+)amphetamine stimulus generalized to all of the agents investigated".[30] A second study in which rats trained to discriminate either 0.75 mg/kg S(+)-amphetamine or 1.5 mg/kg fenfluramine from saline generalized to aminorex as amphetamine stimulus but not to fenfluramine.[31] Rats trained to discriminate 8 mg/kg cocaine from saline generalized 4-methylaminorex to cocaine-stimulus.[32] The reinforcing effects of cis-4-methylaminorex were determined in two models of intravenous drug self-administration in primates. Vehicle or 4-methylaminorex doses were substituted for cocaine. One of the two different doses of 4-methylaminorex maintained self-administration behavior above vehicle control levels.[33]

References

  1. ↑ "2-amino-5-aryloxazoline compositions and methods of using same" US patent 3278382
  2. ↑ 2.0 2.1 2.2 "Synthesis of trans-4-methylaminorex from norephedrine and potassium cyanate.". Microgram Journal 3 (3–4): 154. 2005. https://forendex.southernforensic.org/uploads/references/MicrogramJournal/3.3-4.154.165.pdf. 
  3. ↑ "4-Methylaminorex Synth w/o CNBr". chemistry.mdma.ch. 3 September 2002. https://chemistry.mdma.ch/hiveboard/novel/000212038.html. 
  4. ↑ "Erowid 4-methylaminorex Vault : Dosage". http://www.erowid.org/chemicals/4_methylaminorex/4_methylaminorex_dose.shtml. 
  5. ↑ "System Timed Out (Library of Congress Online Catalog)". http://catalog.loc.gov/cgi-bin/Pwebrecon.cgi?v1=1&ti=1,1&Search%5FArg=Psychotropic%20drugs%20and%20related%20compounds&Search%5FCode=TALL&CNT=25&PID=22167&SEQ=20070902171132&SID=1. 
  6. ↑ "Method of decongesting the nose ... - Google Patents". https://patents.google.com/patent/US4980364. 
  7. ↑ "A fatality involving U4Euh, a cyclic derivative of phenylpropanolamine". Journal of Forensic Sciences 33 (2): 549–53. March 1988. doi:10.1520/JFS11971J. PMID 3373171. 
  8. ↑ "Detection and assay of cis- and trans-isomers of 4-methylaminorex in urine, plasma and tissue samples". Forensic Science International 121 (1–2): 57–64. September 2001. doi:10.1016/S0379-0738(01)00453-4. PMID 11516888. 
  9. ↑ "Pharmacokinetics and tissue distribution of the stereoisomers of 4-methylaminorex in the rat". The Journal of Pharmacology and Experimental Therapeutics 309 (3): 1198–205. June 2004. doi:10.1124/jpet.103.060053. PMID 14742748. 
  10. ↑ 10.0 10.1 "Recreational use of aminorex and pulmonary hypertension". Chest 118 (5): 1496–7. November 2000. doi:10.1378/chest.118.5.1496. PMID 11083709. http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=11083709. 
  11. ↑ "Neurochemical effects of an acute treatment with 4-methylaminorex: a new stimulant of abuse". European Journal of Pharmacology 180 (1): 103–11. May 1990. doi:10.1016/0014-2999(90)90597-Y. PMID 1973111. 
  12. ↑ "Response of monoaminergic and neuropeptide systems to 4-methylaminorex: a new stimulant of abuse". European Journal of Pharmacology 218 (2–3): 287–93. August 1992. doi:10.1016/0014-2999(92)90181-3. PMID 1358636. 
  13. ↑ "The effects of aminorex and related compounds on brain monoamines and metabolites in CBA mice". The Journal of Pharmacy and Pharmacology 49 (1): 89–96. January 1997. doi:10.1111/j.2042-7158.1997.tb06758.x. PMID 9120777. 
  14. ↑ "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence 147: 1–19. February 2015. doi:10.1016/j.drugalcdep.2014.12.005. PMID 25548026. 
  15. ↑ Forsyth, Andrea N (22 May 2012). Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines. https://scholarworks.uno.edu/td/1436/. Retrieved 4 November 2024. 
  16. ↑ 16.0 16.1 16.2 16.3 16.4 "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. 
  17. ↑ 17.0 17.1 17.2 "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. 
  18. ↑ "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology 38 (4): 552–562. March 2013. doi:10.1038/npp.2012.204. PMID 23072836. 
  19. ↑ 19.0 19.1 19.2 "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substrates". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc. NIDA Res Monogr. 180. 1999. pp. 1–476 (252). https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261. "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." 
  20. ↑ "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology 37 (5): 1192–1203. April 2012. doi:10.1038/npp.2011.304. PMID 22169943. 
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 "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. 2014. doi:10.1002/dta.1668. PMID 24841869. 
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 22.6 22.7 22.8 "DARK Classics in Chemical Neuroscience: Aminorex Analogues". ACS Chem Neurosci 9 (10): 2484–2502. October 2018. doi:10.1021/acschemneuro.8b00415. PMID 30269490. "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. [...] As mentioned before, in contrast to other amphetamine-type stimulants, 4,4'-DMAR does not interact with TAAR1 and therefore lacks the auto-inhibitory pathway that attenuates monoamine release and mediates the neuroprotective effects231,232. It has however been shown that many psychoactive compounds stimulate human TAAR1 less potently than the receptor’s rodent counterparts184.". 
  23. ↑ 23.0 23.1 23.2 23.3 "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. July 2015. doi:10.1002/dta.1732. PMID 25331619. 
  24. ↑ 24.0 24.1 "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology 479 (1–3): 23–40. October 2003. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135. 
  25. ↑ 25.0 25.1 "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. 
  26. ↑ 26.0 26.1 26.2 26.3 "Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR". Neurotoxicology 72: 95–100. May 2019. doi:10.1016/j.neuro.2019.02.011. PMID 30776375. Bibcode: 2019NeuTx..72...95R. "The methylated aminorex derivatives investigated in the present study did not interacted with TAAR1 receptors in contrast to amphetamine, MDMA, and several other phenethylamine derivatives (Revel et al., 2012; Simmler et al., 2016). Other aminorex-like ring-substituted 2- aminooxazolines have been shown to interact with TAAR1 receptors (Galley et al., 2016). However, they did not contain a 4-methyl group in contrast to the currently investigated compounds. Activity at TAAR1 may have auto-inhibitory effects on the monoaminergic action of amphetamine-type substances (Di Cara et al., 2011; Simmler et al., 2016). Therefore, the presently investigated compounds that did not bind to TAAR1 may exhibit greater stimulant properties compared to other amphetamines that also bind to TAAR1.". 
  27. ↑ 27.0 27.1 27.2 "The psychostimulant (±)-cis-4,4'-dimethylaminorex (4,4'-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters". Neuropharmacology 138: 282–291. August 2018. doi:10.1016/j.neuropharm.2018.06.018. PMID 29908239. "Receptor-binding experiments suggest that 4,4'-DMAR exhibits no – or if at all only poor-affinity towards mouse and rat TAAR1. On the contrary, sub- (rat) and low-micromolar (mouse) affinities towards TAAR1 have been reported for MDMA (Simmler et al., 2013). The exact role of TAAR1 in amphetamine action remains far from being completely understood (Sitte and Freissmuth, 2015). However, TAAR1 appears to exert auto-inhibitory effects on monoaminergic neurons, thus regulates the release of the corresponding monoamines (Revel et al., 2011, 2012). TAAR1 is activated by a subset of amphetamines (Simmler et al., 2016). This observation has been linked to auto-inhibitory and neuroprotective effects of TAAR1 in amphetamine action (Miner et al., 2017; Revel et al., 2012; DiCara et al., 2011; Lindemann et al., 2008). The lack of agonist activity at TAAR1 might further contribute to long-term toxicity of 4,4'-DMAR, thus representing an interesting field for future investigations.". 
  28. ↑ "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther 357 (1): 134–144. April 2016. doi:10.1124/jpet.115.229765. PMID 26791601. https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA. 
  29. ↑ "Trace Amines and Their Receptors". Pharmacol Rev 70 (3): 549–620. July 2018. doi:10.1124/pr.117.015305. PMID 29941461. 
  30. ↑ "Stimulus properties of a new designer drug: 4-methylaminorex ("U4Euh")". Pharmacology, Biochemistry, and Behavior 35 (3): 517–21. March 1990. doi:10.1016/0091-3057(90)90282-M. PMID 1971111. 
  31. ↑ "Aminorex produces stimulus effects similar to amphetamine and unlike those of fenfluramine". Pharmacology, Biochemistry, and Behavior 42 (1): 175–8. May 1992. doi:10.1016/0091-3057(92)90462-O. PMID 1356272. 
  32. ↑ "Cocaine-stimulus generalization to two new designer drugs: methcathinone and 4-methylaminorex". Pharmacology, Biochemistry, and Behavior 45 (1): 229–31. May 1993. doi:10.1016/0091-3057(93)90110-F. PMID 8516363. 
  33. ↑ "Intravenous self-administration of 4-methylaminorex in primates". Drug and Alcohol Dependence 26 (2): 137–44. October 1990. doi:10.1016/0376-8716(90)90120-4. PMID 2242714. 



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