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| Other names | 4-MAR; 4-MAX; McN-822; McN822 |
| Routes of administration | Oral,Vaporized,Insufflated,Injected |
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| Bioavailability | 62% oral; 79% nasal; 91 - 93.5% smoked; 100% IV |
| Metabolism | Hepatic |
| Eliminationhalf-life | 10-19 hours |
| Excretion | Renal |
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| Chemical and physical data | |
| Formula | C10H12N2O |
| Molar mass | 176.219 g·mol−1 |
| 3D model (JSmol) | |
| Chirality | Racemic mixture |
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4-Methylaminorex (4-MAR,4-MAX) is astimulantdrug of the2-amino-5-aryloxazoline group that was first synthesized in 1960 by McNeil Laboratories.[2] It is also known by its street name "U4Euh" ("Euphoria"). It is banned in many countries as astimulant. 4-Methylaminorex has effects comparable tomethamphetamine but with a longerduration.
4-Methylaminorex exists as fourstereoisomers : (±)-cis and (±)-trans. The (±)-cis isomers are the form usedrecreationally.
The (±)-cis isomers [racemate (1:1-mixture) of the (4R,5S)-isomer and the enantiomeric (4S,5R)-isomer] generally synthesized fromdl-phenylpropanolamine in one step bycyclization withcyanogen bromide (sometimes preparedin situ by reactingsodium cyanide withbromine).[3][4]
Alternate synthesis routes generally involve more steps, such as replacing cyanogen bromide with sodium or potassiumcyanate to form an intermediate and then reacting it with concentratedhydrochloric acid. A method reported in microgram replaced the need for a separate addition ofhydrochloric acid by starting with the hydrochloride salt of thedl-phenylpropanolamine but side-products are noted.[3]
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 butdl-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.[3]
4-Methylaminorex can be smoked,insufflated or taken orally.
As ananorectic, theED50 is 8.8 mg/kg in rats for the (±)-cis isomers. The (±)-trans isomers are slightly more potent at 7.0 mg/kg. As arecreational drug, the effective dosage ranges from 5 to 25 mg.[5]
In the 1970sMcNeil 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/kgp.o for mice[6]
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.[7]
It produces long-lasting effects, generally up to 16 hours in duration if taken orally and up to 12 hours if smoked orinsufflated. Large doses have been reported anecdotally to last up to 36 hours. The effects arestimulant in nature, producingeuphoria, increased attention, and increasedcognition. Anecdotally, it has been reported to produce effects similar tonootropics. 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 asmethylphenidate anddextroamphetamine.
| 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: in blood 21.3 mg/L; in urine 12.3 mg/L. Diazepam concentration in blood was 0.8 mg/L.[8] 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".[9]
Another study focused on pharmacokinetics and tissue distribution of the stereoisomers of 4-methylaminorex in rats.[10]
"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."[11]
There have been three studies studying possibleneurotoxicity of 4-methylaminorex. First study[12] 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 intryptophan 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 thanmethamphetamine orMDMA."
A study[13] 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[14] (using mice) was not able to find any long-term effects suggesting neurotoxicity and instead found anincrease 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 ofaminorex 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 except4S,5S-dimethylaminorex, unlikeMDMA orfenfluramine, 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).[11]
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 inDA,DOPAC orHVA levels." and again later studies [12-13] didn't find any long-term reduction.
| Compound | NETooltip Norepinephrine | DATooltip Dopamine | 5-HTTooltip Serotonin | Ref |
|---|---|---|---|---|
| Phenethylamine | 10.9 | 39.5 | >10,000 | [15][16][17] |
| Dextroamphetamine | 6.6–10.2 | 5.8–24.8 | 698–1,765 | [18][19][17][20] |
| Dextromethamphetamine | 12.3–14.3 | 8.5–40.4 | 736–1,292 | [18][21][17][20] |
| Aminorex | 15.1–26.4 | 9.1–49.4 | 193–414 | [18][22][17][23][20] |
| cis-4-MAR | 4.8 | 1.7 | 53.2 | [23][22] |
| cis-4,4'-DMAR | 11.8–31.6 | 8.6–24.4 | 17.7–59.9 | [22][24][23] |
| trans-4,4'-DMAR | 31.6 | 24.4 | 59.9 | [24][23] |
| cis-MDMAR | 14.8 | 10.2 | 43.9 | [24] |
| trans-MDMAR | 38.9 | 36.2 | 73.4 | [24] |
| Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. Theassays were done in rat brainsynaptosomes and humanpotencies may be different. See alsoMonoamine releasing agent § Activity profiles for a larger table with more compounds.Refs:[25][26] | ||||
4-MAR acts as a highlypotentmonoamine releasing agent (MRA).[23][22] It is specifically anorepinephrine–dopamine releasing agent (NDRA) with weak effects onserotonin.[22][23] The drug'sEC50Tooltip half-maximal effective concentration values for induction ofmonoamine neurotransmitter release have been found to be 4.8 nM fornorepinephrine, 1.7 nM fordopamine, and 53.2 nM forserotonin.[22] It is among the most potent andselectivedopamine releasing agents (DRAs) known.[22][25][26][17]
In contrast to many other MRAs, 4-MAR is inactive at the mouse and rattrace amine-associated receptor 1 (TAAR1).[27] Similarly,4,4'-dimethylaminorex (4,4'-DMAR) is inactive at the mouse and rat TAAR1.[27][23][28] Many othermonoamine releasing agents (MRAs), such as manyamphetamines, are rodent and/or human TAAR1 agonists.[29][30] Activation of the TAAR1 may auto-inhibit and thereby constrain themonoaminergic effects of these agents.[23][28][27] Lack of TAAR1 agonism in the case of aminorexanalogues might enhance their effects relative to MRAs possessing TAAR1 agonism.[23][28][27]
The results of animal experiments conducted with this drug suggest that it has an abuse liability similar tococaine 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".[31] A second study in which rats trained to discriminate either 0.75 mg/kg S(+)-amphetamine or 1.5 mg/kgfenfluramine from saline generalized to aminorex as amphetamine stimulus but not to fenfluramine.[32] Rats trained to discriminate 8 mg/kg cocaine from saline generalized 4-methylaminorex to cocaine-stimulus.[33] 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.[34]
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.
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.
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.
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.
