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Aminorex

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 It was withdrawn from the market after it was found to cause pulmonary hypertension.[2] In the U.S., it is an illegal Schedule I drug, meaning it has high abuse potential, no accepted medical use, and a poor safety profile.

Aminorex
Skeletal formula
Ball-and-stick model of aminorex
Clinical data
ATC code
  • none
Legal status
Legal status
Identifiers
  • (RS)-5-Phenyl-4,5-dihydro-1,3-oxazol-2-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.164.420 Edit this at Wikidata
Chemical and physical data
FormulaC9H10N2O
Molar mass162.192 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • NC1=NCC(C2=CC=CC=C2)O1
  • InChI=1S/C9H10N2O/c10-9-11-6-8(12-9)7-4-2-1-3-5-7/h1-5,8H,6H2,(H2,10,11) checkY
  • Key:SYAKTDIEAPMBAL-UHFFFAOYSA-N checkY
  (verify)

Aminorex, in the 2-amino-5-aryl oxazoline class, was developed by McNeil Laboratories in 1962.[3] 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.[4] It can be produced as a metabolite of the worming medication levamisole, which is sometimes used as a cutting agent of illicitly produced cocaine.[5][6]

Pharmacology

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Pharmacodynamics

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Aminorex is a serotonin–norepinephrine–dopamine releasing agent (SNDRA).[7][8][9] 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.[7][8][9] In addition to its monoamine-releasing activity, aminorex is a weak agonist of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors.[8] Its EC50 values for activation of these receptors are 4,365 nM for 5-HT2A, 870 nM for 5-HT2B, and 525 nM for 5-HT2C.[8]

Activation of serotonin 5-HT2B 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.[8][7][10][9] However, its EC50 for serotonin 5-HT2B 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-HT2B receptor agonism of dexnorfenfluramine.[8] This seems to call into question the role of direct agonism of the serotonin 5-HT2B receptor in the toxicity of aminorex.[8] 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.[8] However, it is possible that metabolites of aminorex and chlorphentermine might be more potent in this action.[8]

History

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It was discovered in 1962 by Edward John Hurlburt,[11] 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.[4][12]

Synthesis

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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.[13] A similar synthesis has been also published.[14] In a search for a cheaper synthetic route, a German team developed an alternative route[15] which, by using chiral styrene oxide, allows an enantiopure product.

See also

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References

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  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. ^ a b 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. ^ a b c 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. ^ a b c d e f g h i 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. ^ a b c 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 
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