Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and 4-Methylaminorex: Difference between pages

{{Short description|Group of stereoisomers}}

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 477222609

| IUPAC_name = 4-Methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine

| alt = Skeletal formula

| image2 = 4-Methylaminorex molecule ball.png

| alt2 = Ball-and-stick model of 4-methylaminorex

| chirality = [[Racemic mixture]]

| tradename =

| legal_BR = F2

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-07-24 |title=RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |url-status=live |archive-url=https://web.archive.org/web/20230827163149/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |archive-date=2023-08-27 |access-date=2023-08-27 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-07-25}}</ref>

| legal_DE = Anlage I

| legal_UN = P I

| routes_of_administration = [[mouth|Oral]], [[Vaporize]]d, [[wikt:insufflation|Insufflated]], [[Intravenous infusion|Injected]]

| index2_label = (±)-cis

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 3568-94-3

| CAS_number2_Ref = {{cascite|correct|CAS}}

| CAS_number2 = 29493-77-4

| KEGG = C22731

| UNII2_Ref = {{fdacite|correct|FDA}}

| UNII2 = 2149QZM652

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 7PK6VC94OU

| C=10 | H=12 | N=2 | O=1

| smiles = CC1C(C2=CC=CC=C2)OC(N)=N1

'''4-Methylaminorex''' ('''4-MAR''', '''4-MAX''') is a [[stimulant]] [[drug]] of the 2-[[amino]]-5-[[aryl]]oxazoline class that was first synthesized in 1960 by McNeil Laboratories.<ref>{{cite patent | country = US | number = 3278382 | title = 2-amino-5-aryloxazoline compositions and methods of using same }}</ref> 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.

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".<ref>{{cite journal | vauthors = Glennon RA, Misenheimer B | title = Stimulus properties of a new designer drug: 4-methylaminorex ("U4Euh") | journal = Pharmacology, Biochemistry, and Behavior | volume = 35 | issue = 3 | pages = 517–21 | date = March 1990 | pmid = 1971111 | doi = 10.1016/0091-3057(90)90282-M | s2cid = 10464868 }}</ref> A second study in which rats trained to discriminate either 0.75&nbsp;mg/kg S(+)-amphetamine or 1.5&nbsp;mg/kg [[fenfluramine]] from saline generalized to aminorex as amphetamine stimulus but not to fenfluramine.<ref>{{cite journal | vauthors = Young R | title = Aminorex produces stimulus effects similar to amphetamine and unlike those of fenfluramine | journal = Pharmacology, Biochemistry, and Behavior | volume = 42 | issue = 1 | pages = 175–8 | date = May 1992 | pmid = 1356272 | doi = 10.1016/0091-3057(92)90462-O | s2cid = 31002190 }}</ref> Rats trained to discriminate 8&nbsp;mg/kg cocaine from saline generalized 4-methylaminorex to cocaine-stimulus.<ref>{{cite journal | vauthors = Young R, Glennon RA | title = Cocaine-stimulus generalization to two new designer drugs: methcathinone and 4-methylaminorex | journal = Pharmacology, Biochemistry, and Behavior | volume = 45 | issue = 1 | pages = 229–31 | date = May 1993 | pmid = 8516363 | doi = 10.1016/0091-3057(93)90110-F | s2cid = 7648152 }}</ref> 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.<ref>{{cite journal | vauthors = Mansbach RS, Sannerud CA, Griffiths RR, Balster RL, Harris LS | title = Intravenous self-administration of 4-methylaminorex in primates | journal = Drug and Alcohol Dependence | volume = 26 | issue = 2 | pages = 137–44 | date = October 1990 | pmid = 2242714 | doi = 10.1016/0376-8716(90)90120-4 }}</ref>

==Chemistry==

4-Methylaminorex exists as four [[stereoisomer]]s : (±)-''cis'' and (±)-''trans''. The (±)-''cis'' isomers are the form used [[Recreational drug|recreationally]].

The (±)-''cis'' isomers [racemate (1:1-mixture) of the (4''R'',5''S'')-isomer and the enantiomeric (4''S'',5''R'')-isomer] generally synthesized from [[phenylpropanolamine|dl-phenylpropanolamine]] in one step by [[cyclization]] with [[cyanogen bromide]] (sometimes prepared ''[[In situ#Chemistry and chemical engineering|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 [[phenylpropanolamine|dl-phenylpropanolamine]] but side-products are noted. The (±)-''trans'' isomers [racemate (1:1-mixture) of the (4''S'',5''S'')-isomer and the enantiomeric (4''R'',5''R'')-isomer] are synthesized in the same manner above but [[norephedrine|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, [[Insufflation (medicine)|insufflated]] or taken orally.

As an [[anorectic]], the [[Effective dose (pharmacology)|ED50]] is 8.8&nbsp;mg/kg in rats for the (±)-''cis'' isomers. The (±)-''trans'' isomers are slightly more potent at 7.0&nbsp;mg/kg. As a [[recreational drug]], the effective dosage ranges from 5 to 25&nbsp;mg.<ref name="titleErowid 4-methylaminorex Vault : Dosage">{{cite web |url=http://www.erowid.org/chemicals/4_methylaminorex/4_methylaminorex_dose.shtml |title=Erowid 4-methylaminorex Vault : Dosage |access-date=2006-11-22 |archive-date=2007-05-26 |archive-url=https://web.archive.org/web/20070526045900/http://www.erowid.org/chemicals/4_methylaminorex/4_methylaminorex_dose.shtml |url-status=live }}</ref>

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&nbsp;mg/kg of body weight. They mention also LD50: 17&nbsp;mg/kg

p.o for mice <ref name="titleSystem Timed Out (Library of Congress Online Catalog)">{{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) |access-date=2007-09-02 |archive-date=2021-05-31 |archive-url=https://web.archive.org/web/20210531152317/https://catalog.loc.gov/legacy.html |url-status=live }}</ref>

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&nbsp;mg/kg of body weight.<ref name="titleMethod of decongesting the nose ... - Google Patents">{{cite web |url=https://patents.google.com/patent/US4980364 |title=Method of decongesting the nose ... - Google Patents }}</ref>

==Effects==

It produces long-lasting effects, generally up to 16 hours in duration if taken orally and up to 12 hours if smoked or [[Insufflation (medicine)|insufflated]]. Large doses have been reported anecdotally to last up to 36 hours. The effects are [[stimulant]] in nature, producing [[Euphoria (emotion)|euphoria]], increased attention, and increased [[cognition]]. Anecdotally, it has been reported to produce effects similar to [[nootropic]]s. 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]].

{| class="wikitable" style="float:right; border:1px solid #BBB;margin:.46em 0 0 .2em"

|-

! 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&nbsp;mg/L; in urine 12.3&nbsp;mg/L. Diazepam concentration in blood was 0.8&nbsp;mg/L.<ref>{{cite journal | vauthors = Davis FT, Brewster ME | title = A fatality involving U4Euh, a cyclic derivative of phenylpropanolamine | journal = Journal of Forensic Sciences | volume = 33 | issue = 2 | pages = 549–53 | date = March 1988 | pmid = 3373171 | doi = 10.1520/JFS11971J}}</ref> 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".<ref>{{cite journal | vauthors = 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 Science International | volume = 121 | issue = 1–2 | pages = 57–64 | date = September 2001 | pmid = 11516888 | doi = 10.1016/S0379-0738(01)00453-4 }}</ref>

Another study focused on pharmacokinetics and tissue distribution of the stereoisomers of 4-methylaminorex in rats.<ref>{{cite journal | vauthors = 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 = The Journal of Pharmacology and Experimental Therapeutics | volume = 309 | issue = 3 | pages = 1198–205 | date = June 2004 | pmid = 14742748 | doi = 10.1124/jpet.103.060053 | s2cid = 28124406 }}</ref>

"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."<ref name="Gaine SP, Rubin LJ, Kmetzo JJ, Palevsky HI, Traill TA 2000 1496–7">{{cite journal | vauthors = 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 | date = November 2000 | pmid = 11083709 | doi = 10.1378/chest.118.5.1496 | url = http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=11083709 | url-status = dead | archive-url = https://archive.today/20130112175859/http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=11083709 | archive-date = 2013-01-12 }}</ref>

==Neurotoxicity studies==

There have been three studies studying possible [[neurotoxicity]] of 4-methylaminorex. First study<ref>{{cite journal | vauthors = 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 = European Journal of Pharmacology | volume = 180 | issue = 1 | pages = 103–11 | date = May 1990 | pmid = 1973111 | doi = 10.1016/0014-2999(90)90597-Y }}</ref> 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&nbsp;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<ref>{{cite journal | vauthors = 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 = European Journal of Pharmacology | volume = 218 | issue = 2–3 | pages = 287–93 | date = August 1992 | pmid = 1358636 | doi = 10.1016/0014-2999(92)90181-3 }}</ref> published 2 years later than first one also suggested reduction in tryptophan hydroxylase activity, they used quite high dose too (10&nbsp;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<ref>{{cite journal | vauthors = 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 = The Journal of Pharmacy and Pharmacology | volume = 49 | issue = 1 | pages = 89–96 | date = January 1997 | pmid = 9120777 | doi = 10.1111/j.2042-7158.1997.tb06758.x | s2cid = 20224300 | doi-access = free }}</ref> (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&nbsp;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).<ref name="Gaine SP, Rubin LJ, Kmetzo JJ, Palevsky HI, Traill TA 2000 1496–7"/>

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 [[Dopamine|DA]], [[DOPAC]] or [[Homovanillic acid|HVA]] levels." and again later studies [12-13] didn't find any long-term reduction.

== References ==

{{Reflist|2}}

== External links ==

* [http://erowid.org/chemicals/4_methylaminorex/4_methylaminorex.shtml Erowid's 4-methylaminorex Vault]

{{Stimulants}}

{{Monoamine releasing agents}}

{{DEFAULTSORT:Methyl-Aminorex, 4-}}

[[Category:Aminorexes]]

[[Category:Beta-Hydroxyamphetamines]]

[[Category:Designer drugs]]

[[Category:Euphoriants]]

[[Category:Serotonin-norepinephrine-dopamine releasing agents]]

[[Category:Stimulants]]