4-Methylaminorex

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4-Methylaminorex
4-Methyl-Aminorex.svg
4-Methylaminorex molecule ball.png
Clinical data
Routes of
administration 		Oral, Vaporized, Insufflated, Injected
Legal status
Legal status
Pharmacokinetic data
Bioavailability 62% oral; 79% nasal; 91 - 93.5% smoked; 100% IV
Metabolism Hepatic
Elimination half-life 10-19 hours
Excretion Renal
Identifiers
  • 4-Methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
Formula C10H12N2O
Molar mass 176.219 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • CC1C(C2=CC=CC=C2)OC(N)=N1
  • 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) Yes check.svgY
  • Key:LJQBMYDFWFGESC-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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. [2] 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.

Contents

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).

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. [3]

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 [4]

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. [5]

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)Urinary levels (μg/ml)
0-645
6-241.0
24-360.1
36-48not 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. [6] 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". [7]

Another study focused on pharmacokinetics and tissue distribution of the stereoisomers of 4-methylaminorex in rats. [8]

"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." [9]

Neurotoxicity studies

There have been three studies studying possible neurotoxicity of 4-methylaminorex. First study [10] 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 [11] 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 [12] (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). [9]

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-Methylaminorex
Compound NE Tooltip Norepinephrine DA Tooltip Dopamine 5-HT Tooltip SerotoninRef
Phenethylamine 10.939.5>10,000 [13] [14] [15]
Dextroamphetamine 6.6–10.25.8–24.8698–1,765 [16] [17] [15] [18]
Dextromethamphetamine 12.3–14.38.5–40.4736–1,292 [16] [19] [15] [18]
Aminorex 15.1–26.49.1–49.4193–414 [16] [20] [15] [21] [18]
cis-4-MAR 4.81.753.2 [21] [20]
cis-4,4'-DMAR 11.8–31.68.6–24.417.7–59.9 [20] [22] [21]
trans-4,4'-DMAR 31.624.459.9 [22] [21]
cis-MDMAR 14.810.243.9 [22]
trans-MDMAR 38.936.273.4 [22]
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: [23] [24]

4-MAR acts as a highly potent monoamine releasing agent (MRA). [21] [20] It is specifically a norepinephrine–dopamine releasing agent (NDRA) with weak effects on serotonin. [20] [21] The drug's EC50 Tooltip half-maximal effective concentration 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. [20] It is among the most potent and selective dopamine releasing agents (DRAs) known. [20] [23] [24] [15]

In contrast to many other MRAs, 4-MAR is inactive at the mouse and rat trace amine-associated receptor 1 (TAAR1). [25] Similarly, 4,4'-dimethylaminorex (4,4'-DMAR) is inactive at the mouse and rat TAAR1. [25] [21] [26] Many other monoamine releasing agents (MRAs), such as many amphetamines, are rodent and/or human TAAR1 agonists. [27] [28] Activation of the TAAR1 may auto-inhibit and thereby constrain the monoaminergic effects of these agents. [21] [26] [25] Lack of TAAR1 agonism in the case of aminorex analogues might enhance their effects relative to MRAs possessing TAAR1 agonism. [21] [26] [25]

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". [29] 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. [30] Rats trained to discriminate 8 mg/kg cocaine from saline generalized 4-methylaminorex to cocaine-stimulus. [31] 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. [32]

Related Research Articles

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<span class="mw-page-title-main">Phenmetrazine</span> Chemical compound

Phenmetrazine, sold under the brand name Preludin among others, is a stimulant drug first synthesized in 1952 and originally used as an appetite suppressant, but withdrawn from the market in the 1980s due to widespread misuse. It was initially replaced by its analogue phendimetrazine which functions as a prodrug to phenmetrazine, but now it is rarely prescribed, due to concerns of misuse and addiction. Chemically, phenmetrazine is a substituted amphetamine containing a morpholine ring or a substituted phenylmorpholine.

<span class="mw-page-title-main">Aminorex</span> Chemical compound

Aminorex, sold under the brand names Menocil and Apiquel among others, is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension (PPH). In the United States, aminorex is a Schedule I controlled substance.

<span class="mw-page-title-main">Chlorphentermine</span> Weight loss medication

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<span class="mw-page-title-main">Naphthylaminopropane</span> Chemical compound

Naphthylaminopropane, also known as naphthylisopropylamine (NIPA), is an experimental drug of the amphetamine and naphthylaminopropane families that was under investigation for the treatment of alcohol and stimulant addiction.

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<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

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<span class="mw-page-title-main">Dopamine releasing agent</span> Type of drug

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain.

<span class="mw-page-title-main">4-Methylamphetamine</span> Stimulant and anorectic drug of the amphetamine class

4-Methylamphetamine (4-MA), also known by the former proposed brand name Aptrol, is a stimulant and anorectic drug of the amphetamine family. It is structurally related to mephedrone (4-methylmethcathinone).

<span class="mw-page-title-main">4-Methylmethamphetamine</span> Stimulant and entactogen drug of the amphetamine class

4-Methylmethamphetamine (4-MMA), also known as mephedrine, is a putative stimulant and entactogen drug of the amphetamine family. It acts as a serotonin–norepinephrine–dopamine releasing agent (SNDRA). The drug is the β-deketo analogue of mephedrone and the N-methyl analogue of 4-methylamphetamine (4-MA).

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<span class="mw-page-title-main">4,4'-Dimethylaminorex</span> Chemical compound

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<span class="mw-page-title-main">Methamnetamine</span> Chemical compound

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<span class="mw-page-title-main">MDMAR</span> Chemical compound

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<span class="mw-page-title-main">2-Phenylmorpholine</span> Pharmaceutical compound

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<span class="mw-page-title-main">Substituted naphthylethylamine</span>

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<span class="mw-page-title-main">Naphthylmorpholine</span> Pharmaceutical compound

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References

  1. ↑ Anvisa (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  2. ↑ US 3278382,"2-amino-5-aryloxazoline compositions and methods of using same"
  3. ↑ "Erowid 4-methylaminorex Vault : Dosage". Archived from the original on 2007-05-26. Retrieved 2006-11-22.
  4. ↑ "System Timed Out (Library of Congress Online Catalog)". Archived from the original on 2021-05-31. Retrieved 2007-09-02.
  5. ↑ "Method of decongesting the nose ... - Google Patents".
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. 1 2 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC   4297708 . PMID   25548026.
  14. ↑ Forsyth, Andrea N (22 May 2012). "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO. Retrieved 4 November 2024.
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  17. ↑ Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW (March 2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC   3572453 . PMID   23072836.
  18. 1 2 3 Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB (1999). "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc (PDF). NIDA Res Monogr. Vol. 180. pp. 1–476 (252). PMID   11680410. 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.
  19. ↑ Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (April 2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC   3306880 . PMID   22169943.
  20. 1 2 3 4 5 6 7 Brandt SD, Baumann MH, Partilla JS, Kavanagh PV, Power JD, Talbot B, Twamley B, Mahony O, O'Brien J, Elliott SP, Archer RP, Patrick J, Singh K, Dempster NM, Cosbey SH (2014). "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. doi:10.1002/dta.1668. PMC   4128571 . PMID   24841869.
  21. 1 2 3 4 5 6 7 8 9 Maier J, Mayer FP, Brandt SD, Sitte HH (October 2018). "DARK Classics in Chemical Neuroscience: Aminorex Analogues". ACS Chem Neurosci. 9 (10): 2484–2502. doi:10.1021/acschemneuro.8b00415. PMC   6287711 . 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.
  22. 1 2 3 4 McLaughlin G, Morris N, Kavanagh PV, Power JD, Twamley B, O'Brien J, Talbot B, Dowling G, Mahony O, Brandt SD, Patrick J, Archer RP, Partilla JS, Baumann MH (July 2015). "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. doi:10.1002/dta.1732. PMC   5331736 . PMID   25331619.
  23. 1 2 Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID   14612135.
  24. 1 2 Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID   17017961.
  25. 1 2 3 4 Rickli A, Kolaczynska K, Hoener MC, Liechti ME (May 2019). "Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR". Neurotoxicology. 72: 95–100. doi:10.1016/j.neuro.2019.02.011. PMID   30776375. 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.
  26. 1 2 3 Maier J, Mayer FP, Luethi D, Holy M, Jäntsch K, Reither H, Hirtler L, Hoener MC, Liechti ME, Pifl C, Brandt SD, Sitte HH (August 2018). "The psychostimulant (±)-cis-4,4'-dimethylaminorex (4,4'-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters". Neuropharmacology. 138: 282–291. 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.
  27. ↑ Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME (April 2016). "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther. 357 (1): 134–144. doi:10.1124/jpet.115.229765. PMID   26791601.
  28. ↑ Gainetdinov RR, Hoener MC, Berry MD (July 2018). "Trace Amines and Their Receptors". Pharmacol Rev. 70 (3): 549–620. doi: 10.1124/pr.117.015305 . PMID   29941461.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
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