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Aminorex

Clinical data
ATC code	none
Legal status
Legal status	BR: Class B2 (Anorectic drugs) CA: Schedule III DE: Anlage II (Authorized trade only, not prescriptible) UK: Class C US: Schedule I
Identifiers
IUPAC name (RS)-5-Phenyl-4,5-dihydro-1,3-oxazol-2-amine
CAS Number	2207-50-3
PubChem CID	16630
DrugBank	DB01490
ChemSpider	15767
UNII	2SH16612I9
KEGG	D02909
ChEMBL	ChEMBL106258
CompTox Dashboard (EPA)	DTXSID00862867
ECHA InfoCard	100.164.420
Chemical and physical data
Formula	C9H10N2O
Molar mass	162.192 g·mol
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES NC1=NCC(C2=CC=CC=C2)O1
InChI InChI=1S/C9H10N2O/c10-9-11-6-8(12-9)7-4-2-1-3-5-7/h1-5,8H,6H2,(H2,10,11) Key:SYAKTDIEAPMBAL-UHFFFAOYSA-N
(verify)

Aminorex (Menocil, Apiquel, aminoxaphen, aminoxafen, McN-742) is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension. In the U.S., it is an illegal Schedule I drug.

Aminorex, in the 2-amino-5-aryl oxazoline class, was developed by McNeil Laboratories in 1962. It is closely related to 4-methylaminorex. Aminorex has been shown to have locomotor stimulant effects, lying midway between dextroamphetamine and methamphetamine. Aminorex effects have been attributed to the release of catecholamines. It can be produced as a metabolite of the worming medication levamisole, which is sometimes used as a cutting agent of illicitly produced cocaine.

Pharmacology

Pharmacodynamics

Aminorex is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). Its EC₅₀Tooltip half-maximal effective concentration values for induction of monoamine release are 26.4 nM for norepinephrine, 49.4 nM for dopamine, and 193 nM for serotonin. In addition to its monoamine-releasing activity, aminorex is a weak agonist of the serotonin 5-HT₂ receptors, including of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors. Its EC₅₀ values for activation of these receptors are 4,365 nM for 5-HT_2A, 870 nM for 5-HT_2B, and 525 nM for 5-HT_2C.

Activation of serotonin 5-HT_2B receptors by aminorex, either directly via agonism or indirectly via serotonin release, has been implicated in the development of pulmonary arterial hypertension and cardiac valvulopathy with the drug. However, its EC₅₀ for serotonin 5-HT_2B receptor activation is 33-fold higher than its EC₅₀ value for induction of norepinephrine release and is almost 50-fold less potent than the serotonin 5-HT_2B receptor agonism of dexnorfenfluramine. This seems to call into question the role of direct agonism of the serotonin 5-HT_2B receptor in the toxicity of aminorex. Along similar lines, chlorphentermine, a related drug that has also been associated with such adverse effects, shows negligible direct serotonin 5-HT_2B receptor agonistic activity. However, it is possible that metabolites of aminorex and chlorphentermine might be more potent in this action.

History

It was discovered in 1962 by Edward John Hurlburt, and was quickly found in 1963 to have an anorectic effect in rats. It was introduced as a prescription appetite suppressant in Germany, Switzerland and Austria in 1965, but was withdrawn in 1972 after it was found to cause pulmonary hypertension in approximately 0.2% of patients, and was linked to a number of deaths.

Synthesis

The synthesis was first reported in a structure-activity relationship study of 2-amino-5-aryl-2-oxazolines, where aminorex was found to be approximately 2.5 times more potent than D-amphetamine sulfate in inducing anorexia in rats, and was also reported to have CNS stimulant effects.

The racemic synthesis involves addition/cyclization reaction of 2-amino-1-phenylethanol with cyanogen bromide. A similar synthesis has been also published. In a search for a cheaper synthetic route, a German team developed an alternative route which, by using chiral styrene oxide, allows an enantiopure product.

See also

• 4-Methylaminorex
• Clominorex
• Cyclazodone
• Fenozolone
• Fluminorex
• Pemoline
• Thozalinone
• List of aminorex analogues

References

1. Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
2. Gaine SP, Rubin LJ, Kmetzo JJ, Palevsky HI, Traill TA (November 2000). "Recreational use of aminorex and pulmonary hypertension". Chest. 118 (5): 1496–1497. doi:10.1378/chest.118.5.1496. PMID 11083709. Archived from the original on 2013-01-12.
3. US 3161650, Ireland PG, "2-Amino-5-Aryloxazoline Products", issued 15 December 1964, assigned to Janssen Pharmaceuticals Inc. 
4. ^ Fishman AP (Jan 1991). "Aminorex to fen/phen: an epidemic foretold". Circulation. 99 (1): 156–161. doi:10.1161/01.CIR.99.1.156. PMID 9884392.
5. Ho EN, Leung DK, Leung GN, Wan TS, Wong AS, Wong CH, et al. (April 2009). "Aminorex and rexamino as metabolites of levamisole in the horse". Analytica Chimica Acta. 638 (1): 58–68. Bibcode:2009AcAC..638...58H. doi:10.1016/j.aca.2009.02.033. PMID 19298880.
6. Bertol E, Mari F, Milia MG, Politi L, Furlanetto S, Karch SB (July 2011). "Determination of aminorex in human urine samples by GC-MS after use of levamisole". Journal of Pharmaceutical and Biomedical Analysis. 55 (5): 1186–1189. doi:10.1016/j.jpba.2011.03.039. PMID 21531521.
7. ^ Rothman RB, Baumann MH (July 2002). "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacol Ther. 95 (1): 73–88. doi:10.1016/s0163-7258(02)00234-6. PMID 12163129.
8. ^ Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Curr Top Med Chem. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID 17017961.
9. ^ Rothman RB, Baumann MH (April 2002). "Serotonin releasing agents. Neurochemical, therapeutic and adverse effects". Pharmacol Biochem Behav. 71 (4): 825–836. doi:10.1016/s0091-3057(01)00669-4. PMID 11888573.
10. Rothman RB, Baumann MH (2000). "Neurochemical mechanisms of phentermine and fenfluramine: Therapeutic and adverse effects". Drug Development Research. 51 (2): 52–65. doi:10.1002/1098-2299(200010)51:2<52::AID-DDR2>3.0.CO;2-H. ISSN 0272-4391.
11. US 3115494, Albert MG, Ireland PG, "2-amino-5, 6-dihydro-4ii-1, 3-oxazines and a process for their preparation", issued 2 December 1963, assigned to Janssen Pharmaceuticals Inc. 
12. Weigle DS (June 2003). "Pharmacological therapy of obesity: past, present, and future". The Journal of Clinical Endocrinology and Metabolism. 88 (6): 2462–2469. doi:10.1210/jc.2003-030151. PMID 12788841.
13. Poos GI, Carson JR, Rosenau JD, Roszkowski AP, Kelley NM, Mcgowin J (May 1963). "2-Amino-5-aryl-2-oxazolines. Potent New Anorectic Agents". Journal of Medicinal Chemistry. 6 (3): 266–272. doi:10.1021/jm00339a011. PMID 14185981.
14. Ueda S, Terauchi H, Yano A, Ido M, Matsumoto M, Kawasaki M (January 2004). "4,5-Disubstituted-1,3-oxazolidin-2-imine derivatives: a new class of orally bioavailable nitric oxide synthase inhibitor". Bioorganic & Medicinal Chemistry Letters. 14 (2): 313–316. doi:10.1016/j.bmcl.2003.11.010. PMID 14698148.
15. DE 2101424, "2-Amino-5-phenyl-2-oxazoline preparation", assigned to Polska Akademia Nauk Instytut Chemn Organicznej, Warschau 

• Drugs not assigned an ATC code
• 5-HT2B agonists
• 5-HT2C agonists
• Aminorexes
• Anorectics
• Cardiotoxins
• Norepinephrine-dopamine releasing agents
• Respiratory toxins
• Stimulants
• Withdrawn drugs