4-Methylaminorex

4-Methylaminorex (4-MAR, 4-MAX) is a stimulant drug of the 2-amino-5-aryloxazoline class 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
Clinical data
Routes of
administration		Oral, Vaporized, Insufflated, Injected
Legal status
Legal status
  • AU: S9 (Prohibited substance)
  • CA: Schedule III
  • DE: Anlage I (Authorized scientific use only)
  • UK: Class A
  • US: Schedule I
  • UN: Psychotropic Schedule I
Pharmacokinetic data
Bioavailability62% oral; 79% nasal; 91 - 93.5% smoked; 100% IV
MetabolismHepatic
Elimination half-life10-19 hours
ExcretionRenal
Identifiers
IUPAC name
  • 4-Methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
Chemical and physical data
FormulaC10H12N2O
Molar mass176.21 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
SMILES
  • CC1C(C2=CC=CC=C2)OC(N)=N1
InChI
  • InChI=1S/C10H12N2O/c1-7-9(13-10(11)12-7)8-5-3-2-4-6-8/h2-7,9H,1H3,(H2,11,12) Y
  • Key:LJQBMYDFWFGESC-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

4-Methylaminorex has effects comparable to methamphetamine but with a longer duration.

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".[2] 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.[3] Rats trained to discriminate 8 mg/kg cocaine from saline generalized 4-methylaminorex to cocaine-stimulus.[4] 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.[5]

Chemistry

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

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.[6]

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 [7]

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.[8]

Effects

It 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) Concentration of 4-methylaminorex in urine (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: in blood 21.3 mg/L; in urine 12.3 mg/L. Diazepam concentration in blood was 0.8 mg/L.[9] 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".[10]

Another study focused on pharmacokinetics and tissue distribution of the stereoisomers of 4-methylaminorex in rats.[11]

"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."[12]

Neurotoxicity studies

There have been three studies studying possible neurotoxicity of 4-methylaminorex. First study[13] 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[14] 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[15] (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).[12]

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.

References
  1. US 3278382, "2-amino-5-aryloxazoline compositions and methods of using same"
  2. Glennon RA, Misenheimer B (March 1990). "Stimulus properties of a new designer drug: 4-methylaminorex ("U4Euh")". Pharmacology, Biochemistry, and Behavior. 35 (3): 517–21. doi:10.1016/0091-3057(90)90282-M. PMID 1971111. S2CID 10464868.
  3. Young R (May 1992). "Aminorex produces stimulus effects similar to amphetamine and unlike those of fenfluramine". Pharmacology, Biochemistry, and Behavior. 42 (1): 175–8. doi:10.1016/0091-3057(92)90462-O. PMID 1356272. S2CID 31002190.
  4. Young R, Glennon RA (May 1993). "Cocaine-stimulus generalization to two new designer drugs: methcathinone and 4-methylaminorex". Pharmacology, Biochemistry, and Behavior. 45 (1): 229–31. doi:10.1016/0091-3057(93)90110-F. PMID 8516363. S2CID 7648152.
  5. Mansbach RS, Sannerud CA, Griffiths RR, Balster RL, Harris LS (October 1990). "Intravenous self-administration of 4-methylaminorex in primates". Drug and Alcohol Dependence. 26 (2): 137–44. doi:10.1016/0376-8716(90)90120-4. PMID 2242714.
  6. "Erowid 4-methylaminorex Vault : Dosage". Archived from the original on 2007-05-26. Retrieved 2006-11-22.
  7. "System Timed Out (Library of Congress Online Catalog)". Archived from the original on 2021-05-31. Retrieved 2007-09-02.
  8. "Method of decongesting the nose ... - Google Patents".
  9. Davis FT, Brewster ME (March 1988). "A fatality involving U4Euh, a cyclic derivative of phenylpropanolamine". Journal of Forensic Sciences. 33 (2): 549–53. doi:10.1520/JFS11971J. PMID 3373171.
  10. Kankaanpää A, Meririnne E, Ellermaa S, Ariniemi K, Seppälä T (September 2001). "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. doi:10.1016/S0379-0738(01)00453-4. PMID 11516888.
  11. Meririnne E, Ellermaa S, Kankaanpää A, Bardy A, Seppälä T (June 2004). "Pharmacokinetics and tissue distribution of the stereoisomers of 4-methylaminorex in the rat". The Journal of Pharmacology and Experimental Therapeutics. 309 (3): 1198–205. doi:10.1124/jpet.103.060053. PMID 14742748. S2CID 28124406.
  12. Gaine SP, Rubin LJ, Kmetzo JJ, Palevsky HI, Traill TA (November 2000). "Recreational use of aminorex and pulmonary hypertension". Chest. 118 (5): 1496–7. doi:10.1378/chest.118.5.1496. PMID 11083709. Archived from the original on 2013-01-12.
  13. Bunker CF, Johnson M, Gibb JW, Bush LG, Hanson GR (May 1990). "Neurochemical effects of an acute treatment with 4-methylaminorex: a new stimulant of abuse". European Journal of Pharmacology. 180 (1): 103–11. doi:10.1016/0014-2999(90)90597-Y. PMID 1973111.
  14. Hanson GR, Bunker CF, Johnson M, Bush L, Gibb JW (August 1992). "Response of monoaminergic and neuropeptide systems to 4-methylaminorex: a new stimulant of abuse". European Journal of Pharmacology. 218 (2–3): 287–93. doi:10.1016/0014-2999(92)90181-3. PMID 1358636.
  15. Zheng Y, Russell B, Schmierer D, Laverty R (January 1997). "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. doi:10.1111/j.2042-7158.1997.tb06758.x. PMID 9120777. S2CID 20224300.
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