4-Methyl-aminorex

Drugbox
IUPAC_name = 4-methyl-5-phenyl-2-amino-oxazoline

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CAS_number = 3568-94-3
CAS_supplemental = 29493-77-4 - (±)-cis isomers
ATC_prefix=
ATC_suffix=
ATC_supplemental=
PubChem=
smiles = C1=CC=CC(=C1)C2C(N=C(O2)N)C
DrugBank=
C=10 | H=12 | N=2 | O=1
molecular_weight = 176.21
bioavailability= 62% oral; 79% nasal; 91 - 93.5% smoked; 100% IV
metabolism = Hepatic
elimination_half-life= 10-19 hours
excretion = Renal
pregnancy_US = D
legal_US = Schedule I
legal_CA = Schedule III
routes_of_administration= Oral, Vaporized, , Injected

4-Methyl-aminorex, Methylaminorex, or 4-MAR is a stimulant drug of the 2-amino-5-aryloxazoline class. It is banned in many countries as a stimulant.

4-Methylaminorex has effects comparable to methamphetamine but with a much longer duration. Some contend it has fewer side effects.Fact|date=February 2007 Users of 4-methylaminorex generally believe it to be a non-addictive stimulant. Some users say that its effects are somewhat similar to modafinil and pemoline (which are generally considered to have a low risk of dependence) [cite journal |author=Langer DH, Sweeney KP, Bartenbach DE, Davis PM, Menander KB |title=Evidence of lack of abuse or dependence following pemoline treatment: results of a retrospective survey |journal=Drug Alcohol Depend |volume=17 |issue=2-3 |pages=213–27 |year=1986 |month=Jun |pmid=3743405 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0376-8716(86)90009-8] [cite journal |author=Myrick H, Malcolm R, Taylor B, LaRowe S |title=Modafinil: preclinical, clinical, and post-marketing surveillance--a review of abuse liability issues |journal=Ann Clin Psychiatry |volume=16 |issue=2 |pages=101–9 |year=2004 |pmid=15328903 |doi= |url=] although 4-methylaminorex is much stronger than those drugs.

Contrary to these claims, 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, " [s] timulus 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". [cite journal |author=Glennon RA, Misenheimer B |title=Stimulus properties of a new designer drug: 4-methylaminorex ("U4Euh") |journal=Pharmacol. Biochem. Behav. |volume=35 |issue=3 |pages=517–21 |year=1990 |month=Mar |pmid=1971111 |doi= |url=] 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. [cite journal |author=Young R |title=Aminorex produces stimulus effects similar to amphetamine and unlike those of fenfluramine |journal=Pharmacol. Biochem. Behav. |volume=42 |issue=1 |pages=175–8 |year=1992 |month=May |pmid=1356272 |doi= |url=] Rats trained to discriminate 8 mg/kg cocaine from saline generalized 4-methylaminorex to cocaine-stimulus. [cite journal |author=Young R, Glennon RA |title=Cocaine-stimulus generalization to two new designer drugs: methcathinone and 4-methylaminorex |journal=Pharmacol. Biochem. Behav. |volume=45 |issue=1 |pages=229–31 |year=1993 |month=May |pmid=8516363 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0091-3057(93)90110-F] 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. [cite journal |author=Mansbach RS, Sannerud CA, Griffiths RR, Balster RL, Harris LS |title=Intravenous self-administration of 4-methylaminorex in primates |journal=Drug Alcohol Depend |volume=26 |issue=2 |pages=137–44 |year=1990 |month=Oct |pmid=2242714 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0376-8716(90)90120-4]

Chemistry

4-methylaminorex exists as four stereoisomers - (±)-"cis" and (±)-"trans". The (±)-"cis" isomers are the form used recreationally. The (±)-"cis" isomers are 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 sepeate addition of hydrochloric acid by starting with the hydrochloride salt of the dl-phenylpropanolamine but side-products are noted. The (±)-"trans" isomers are synthesized in the same manner above but dl-norpseudoephedrine is used as the starting material instead.

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.cite web |url=http://www.erowid.org/chemicals/4_methylaminorex/4_methylaminorex_dose.shtml |title=Erowid 4-methylaminorex Vault : Dosage |accessdate= |format= |work=]

In the 1970's 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: 17mg/kgp.o for mice cite web |url=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 |title=System Timed Out (Library of Congress Online Catalog) |accessdate= |format= |work=]

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.cite web |url=http://www.google.com/patents?id=XtgbAAAAEBAJ |title=Method of decongesting the nose ... - Google Patents |accessdate= |format= |work=]

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, an increase in 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 any 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, dextroamphetamine and modafinil.

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. [cite journal |author=Davis FT, Brewster ME |title=A fatality involving U4Euh, a cyclic derivative of phenylpropanolamine |journal=J. Forensic Sci. |volume=33 |issue=2 |pages=549–53 |year=1988 |month=Mar |pmid=3373171 |doi= |url=] One rat study [cite journal |author=Kankaanpää A, Meririnne E, Ellermaa S, Ariniemi K, Seppälä T |title=Detection and assay of cis- and trans-isomers of 4-methylaminorex in urine, plasma and tissue samples |journal=Forensic Sci. Int. |volume=121 |issue=1-2 |pages=57–64 |year=2001 |month=Sep |pmid=11516888 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0379-0738(01)00453-4] 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"

Also an another study has studied pharmacokinetics and tissue distribution of the stereoisomers of 4-methylaminorex in rats. [cite journal |author=Meririnne E, Ellermaa S, Kankaanpää A, Bardy A, Seppälä T |title=Pharmacokinetics and tissue distribution of the stereoisomers of 4-methylaminorex in the rat |journal=J. Pharmacol. Exp. Ther. |volume=309 |issue=3 |pages=1198–205 |year=2004 |month=Jun |pmid=14742748 |doi=10.1124/jpet.103.060053 |url=]

"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." [cite journal |author=Gaine SP, Rubin LJ, Kmetzo JJ, Palevsky HI, Traill TA |title=Recreational use of aminorex and pulmonary hypertension |journal=Chest |volume=118 |issue=5 |pages=1496–7 |year=2000 |month=Nov |pmid=11083709 |doi= |url=http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=11083709]

There have been three studies studying possible neurotoxicity of 4-methylaminorex. First study [cite journal |author=Bunker CF, Johnson M, Gibb JW, Bush LG, Hanson GR |title=Neurochemical effects of an acute treatment with 4-methylaminorex: a new stimulant of abuse |journal=Eur. J. Pharmacol. |volume=180 |issue=1 |pages=103–11 |year=1990 |month=May |pmid=1973111 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0014-2999(90)90597-Y] 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 METH or MDMA."

Study [cite journal |author=Hanson GR, Bunker CF, Johnson M, Bush L, Gibb JW |title=Response of monoaminergic and neuropeptide systems to 4-methylaminorex: a new stimulant of abuse |journal=Eur. J. Pharmacol. |volume=218 |issue=2-3 |pages=287–93 |year=1992 |month=Aug |pmid=1358636 |doi= |url=] published 2 years later than first one also suggested reduction in tryptophan hydroxylase activity, they used quite high dose too (10mg/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"

Latest study [cite journal |author=Zheng Y, Russell B, Schmierer D, Laverty R |title=The effects of aminorex and related compounds on brain monoamines and metabolites in CBA mice |journal=J. Pharm. Pharmacol. |volume=49 |issue=1 |pages=89–96 |year=1997 |month=Jan |pmid=9120777 |doi= |url=] (using mice) was not able to find any long term effects suggesting neurotoxicity and they found instead "increase" in serotonin levels, they used quite high doses too(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,SS-dimethylaminorex, unlike MDMA or fenfluramine, are not toxic to either dopamine or 5-HT neurotransmitter systems in CBA mice. It was reported that although multiple doses of 4-methylaminorex caused long-term (7 days) declines in striatal tryptophan hydroxylase activity in SD rats, no changes were found in 5-HT and 5-HIAA levels (Hanson et al 1992). [cite journal |author=Gaine SP, Rubin LJ, Kmetzo JJ, Palevsky HI, Traill TA |title=Recreational use of aminorex and pulmonary hypertension |journal=Chest |volume=118 |issue=5 |pages=1496–7 |year=2000 |month=Nov |pmid=11083709 |doi= |url=http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=11083709]

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.

Legal Status

In the Netherlands, 4-Methylaminorex is a List I drug of the Opium Law. It is not approved by the CBG, and so it is designated as lacking any medical use.

In the US, (±)-"cis"-4-methylaminorex was placed in Schedule I of the Controlled Substances Act shortly after its emergence as a recreational drug in the mid 1980s. Manufacturing the "trans" isomer required a different process that those encountered when the substance was first scheduled, and was believed less potent than the "cis" isomer with a much lower abuse potential.²

However, studies revealing the abuse potential of the 'trans' isomer, coupled with the development of new clandestine synthetic methods that would produce the "trans" created a potential loophole in the law, which covered only the 'cis' isomer.

To clarify the situation, the US Drug Enforcement Administration published a paper in its DEA Microgram Journal, regarding interpretation of the relevant statutory law as it relates to the status of "trans"-4-methylaminorex. In summary, according to this non-legally binding decision, "trans"-4-methylaminorex is not currently a controlled substance, but a potential analog. In fact, the report explicitly states:

"The United States [Drug Enforcment Administration] has the following opinion on the legality of the positional isomer "trans"-4-methylaminorex, which, unlike its 'cis' isomer was never placed in any schedule under the Controlled Substances Act."

However, the opinion does say that the agency considers the substance a potential controlled substance analog, making the substance identical to a Schedule I substance if intended for human consumption, according to the analog act In fact, the report gives an account of a successful conviction under the analog act of an offense involving the 'trans' isomer. The full text, very detailed, sound legalistic interpretation, along with advances in clandestine chemistry that increases the production of the "trans" isomer can be read on the DEA Microgram 2005, Vol. 3 Wikimedia Foundation. 2010.