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| Other names | Aminoxaphen; Aminoxafen; McN-742 |
| Routes of administration | Oral |
| Drug class | Stimulant;Appetite suppressant;Norepinephrine–dopamine releasing agent |
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| ECHA InfoCard | 100.164.420 |
| Chemical and physical data | |
| Formula | C9H10N2O |
| Molar mass | 162.192 g·mol−1 |
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| Chirality | Racemic mixture |
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Aminorex, sold under the brand namesMenocil andApiquel among others, is aweight loss (anorectic)stimulantdrug.[2][3] It waswithdrawn from the market after it was found to causepulmonary hypertension (PPH).[3][4] In theUnited States, aminorex is aSchedule Icontrolled substance.
Aminorex, in the2-amino-5-aryloxazoline group, was developed byMcNeil Laboratories in 1962.[5] It is closely related to4-methylaminorex (4-MAR). Aminorex has been shown to havelocomotor-stimulant effects, lying midway betweendextroamphetamine andmethamphetamine. Aminorex effects have been attributed to the release ofcatecholamines.[6] It can be produced as ametabolite of thedeworming medicationlevamisole, which is very frequently used as acutting agent of illicitly producedcocaine.[7][8]
Aminorex was formerly used as anappetite suppressant.[9]
Aminorex is aserotonin–norepinephrine–dopamine releasing agent (SNDRA).[10][11][12] ItsEC50Tooltip half-maximal effective concentration values forinduction of monoamine release are 26.4 nM fornorepinephrine, 49.4 nM fordopamine, and 193 nM forserotonin.[10][11][12] In addition to its monoamine-releasing activity, aminorex is a weakagonist of theserotonin5-HT2 receptors, including of the serotonin5-HT2A,5-HT2B, and5-HT2C receptors.[11] ItsEC50 values for activation of these receptors are 4,365 nM for 5-HT2A, 870 nM for 5-HT2B, and 525 nM for 5-HT2C.[11]
| Compound | NETooltip Norepinephrine | DATooltip Dopamine | 5-HTTooltip Serotonin | Ref |
|---|---|---|---|---|
| Phenethylamine | 10.9 | 39.5 | >10,000 | [13][14][15] |
| Dextroamphetamine | 6.6–10.2 | 5.8–24.8 | 698–1,765 | [16][17][15][18] |
| Dextromethamphetamine | 12.3–14.3 | 8.5–40.4 | 736–1,292 | [16][19][15][18] |
| Aminorex | 15.1–26.4 | 9.1–49.4 | 193–414 | [16][20][15][9][18] |
| cis-4-MAR | 4.8 | 1.7 | 53.2 | [9][20] |
| cis-4,4'-DMAR | 11.8–31.6 | 8.6–24.4 | 17.7–59.9 | [20][21][9] |
| trans-4,4'-DMAR | 31.6 | 24.4 | 59.9 | [21][9] |
| cis-MDMAR | 14.8 | 10.2 | 43.9 | [21] |
| trans-MDMAR | 38.9 | 36.2 | 73.4 | [21] |
| 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:[22][11] | ||||
Activation of serotonin 5-HT2B receptors by aminorex, either directly via agonism or indirectly via serotonin release, has been implicated in the development ofpulmonary arterial hypertension andcardiac valvulopathy with the drug.[11][10][23][12] However, itsEC50 for serotonin 5-HT2B receptor activation is 33-fold higher than itsEC50 value for induction of norepinephrine release and is almost 50-fold lesspotent than the serotonin 5-HT2B receptor agonism ofdexnorfenfluramine.[11] This seems to call into question the role of direct agonism of the serotonin 5-HT2B receptor in thetoxicity of aminorex.[11] Along similar lines,chlorphentermine, a related drug that has also been associated with such adverse effects, shows negligible direct serotonin 5-HT2B receptor agonistic activity.[11] However, it is possible thatmetabolites of aminorex and chlorphentermine might be more potent in this action.[11]
Aminorex does not appear to have been assessed at thetrace amine-associated receptor 1 (TAAR1).[24][25] However, severalderivatives of aminorex, such as4-methylaminorex (4-MAR) and4,4'-dimethylaminorex (4,4'-DMAR), have been found to be inactive at the mouse and rat TAAR1.[9][26][27] Many othermonoamine releasing agents (MRAs), such as manyamphetamines, are rodent and/or human TAAR1 agonists.[28][29] Activation of the TAAR1 may auto-inhibit and thereby constrain themonoaminergic effects of these agents.[9][26][27] Lack of TAAR1 agonism in the case of aminorexanalogues might enhance their effects relative to MRAs possessing TAAR1 agonism.[9][26][27]
Aminorex is a member of the2-amino-5-phenyloxazoline group.[2] It isstructurally related to thesubstituted amphetamines likeamphetamine and to thesubstituted phenylmorpholines likephenmetrazine.[2]
A variety ofderivatives andanalogues of aminorex are known.[2] These include2'-fluoro-4-methylaminorex (2F-MAR),2C-B-aminorex,3',4'-methylenedioxy-4-methylaminorex (MDMAR),4'-bromo-4-methylaminorex (4B-MAR),4'-chloro-4-methylaminorex (4C-MAR),4'-fluoro-4-methylaminorex (4F-MAR),4-methylaminorex (4-MAR),4,4'-dimethylaminorex (4,4'-DMAR),clominorex,cyclazodone,fenozolone,fluminorex,pemoline, andthozalinone, among others.[2][9][27]
The synthesis was first reported in astructure-activity relationship study of 2-amino-5-aryl-2-oxazolines, where aminorex was found to be approximately 2.5 times more potent thanD-amphetamine sulfate in inducing anorexia in rats, and was also reported to have CNS stimulant effects.
Theracemic synthesis involves addition/cyclization reaction of 2-amino-1-phenylethanol withcyanogen bromide.[30] A similar synthesis has been also published.[31] In a search for a cheaper synthetic route, a German team developed an alternative route[32] which, by using chiral styrene oxide, allows an enantiopure product.
It was discovered in 1962 by Edward John Hurlburt,[33] and was quickly found in 1963 to have ananorectic effect inrats. It was introduced as aprescription appetite suppressant inGermany,Switzerland andAustria in 1965, but was withdrawn in 1972 after it was found to causepulmonary hypertension in approximately 0.2% of patients, and was linked to a number of deaths.[6][34]
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.
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.
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.
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.
