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Glutethimide

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Glutethimide
Clinical data
Trade namesDoriden, Elrodorm, Noxyron, others
Pregnancy
category
  • C: (United States)
Dependence
liability		Moderate - high
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityVariable (Tmax = 1–6 hours)[2]
Protein binding~50%
MetabolismExtensive hepatic
Elimination half-life8–12 hours
ExcretionRenal
Identifiers
  • 3-ethyl-3-phenyl-piperidine-2,6-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.921 Edit this at Wikidata
Chemical and physical data
FormulaC13H15NO2
Molar mass217.268 g·mol−1
3D model (JSmol)
Melting point84 °C (183 °F)
Solubility in water999 mg/L (30 °C/86 °F) mg/mL (20 °C)
  • O=C1NC(CCC1(CC)C2=CC=CC=C2)=O
  • InChI=1S/C13H15NO2/c1-2-13(10-6-4-3-5-7-10)9-8-11(15)14-12(13)16/h3-7H,2,8-9H2,1H3,(H,14,15,16) checkY
  • Key:JMBQKKAJIKAWKF-UHFFFAOYSA-N checkY
  (verify)

Glutethimide (brand name Doriden) is a sedative-hypnotic medication introduced by Ciba Specialty Chemicals in 1954,[3] initially thought to be a safer alternative to barbiturates in the treatment of insomnia. Medical prescriptions of the substance declined in the early 1970s, as it became clear there that glutethimide was equally liable to form addiction and dependency as barbiturates and other depressants frequently used at the time (e.g. methaqualone, methyprylon, ethchlorvynol, ethinamate); abrupt cessation causes symptoms similar to barbiturate withdrawal.

Doriden was manufactured as a scored, white tablet dosed at 500 mg. Commercial production of glutethimide was discontinued in 1993, and in Hungary in 2006.[citation needed] Since 2013, the United States Drug Enforcement Administration has limited annual production of the substance to three grams (equivalent to six Doriden tablets), suggesting current usage is limited small-scale research.[citation needed]

Mechanism of Action

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Glutethimide is a CYP2D6 enzyme inducer, therefore enabling the body to convert higher amounts of codeine to morphine.

Usage

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Long-term Prescription

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Following long-term use, cessation of glutethimide can produce rebound effects resembling those seen in barbiturate withdrawal; anecdotally, patients consistently taking stable doses of the drug long-term have reported symptoms including delirium, hallucinosis, convulsions and fever.[4]

Recreational Use

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Glutethimide is a CYP2D6 enzyme inducer and was often recreationally, taken alongside codeine – a combination referred to on the streets as "hits", "Cibas and codeine", and "Dors and Fours" (as in "Doriden with Tylenol 4) – as it enables the body to convert higher amounts of the codeine to morphine. In conjunction with glutethimide's inherent sedative properties, this was a highly potent and often fatal combination.[5][6]

The demand for this combination in Philadelphia and Pittsburgh, PA; Newark, New Jersey; New York City; Boston, MA; and Baltimore, MD led to small-scale clandestine synthesis of glutethimide since 1984,[7]: 203  a process that is difficult and potentially explosive relative synthesizing similar depressants like ethchlorvynol, methyprylon, or barbiturates.

Clinical Use and Research

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Glutethimide's effect on quickening the transition of codeine to morphine was used and studied clinically, including some research in the 1970s in various countries of using it under carefully monitored circumstances as a form of oral opioid agonist substitution therapy, e.g. as a Substitutionmittel that may be a useful alternative to methadone.[8][9]

Discontinuation

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Commercial production of glutethimide was discontinued in the U.S. in 1993 and in several eastern European countries, notably Hungary, in 2006. Analysis of confiscated glutethimide seems to invariably show the drug or the results of attempted synthesis, as opposed to being "laced" with similar depressants.[7]

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United States

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Glutethimide is a Schedule II drug under the Convention on Psychotropic Substances.[10] It was originally a Schedule III drug in the United States under the Controlled Substances Act, but in 1991 it was upgraded to Schedule II,[11] several years after it was discovered that misuse combined with codeine increased the effect of the codeine and deaths had resulted from the combination.[12][13] It has a DEA ACSCN of 2550 and a 2013 production quota of 3 g.

Synthesis

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The (R) isomer has a faster onset and more potent anticonvulsant activity in animal models than the (S) isomer.[14]

Thieme Synthesis:[15][16][17] Patent:[18][3]

The base catalyzed conjugate addition of 2-phenylbutyronitrile [769-68-6] (1) to ethyl acrylate (2) gives ethyl 4-cyano-4-phenylhexanoate, CID:139890735 (3). Alkaline hydrolysis of the nitrile group into an amide group, and subsequent acidic cyclization of the product affords the desired glutethimide (4).

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. ^ Barceloux DG (2012). Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. Hoboken, N.J.: John Wiley & Sons, Inc. pp. 492–493. ISBN 978-0-471-72760-6. OCLC 814224300.
  3. ^ a b US patent 2673205, Hoffmann K, Tagmann E, "3-Disubstituted Dioxopiperidines and the Manufacture thereof", issued 23 March 1954, assigned to CIBA 
  4. ^ Cookson JC (September 1995). "Rebound exacerbation of anxiety during prolonged tranquilizer ingestion". Journal of the Royal Society of Medicine. 88 (9): 544. PMC 1295346. PMID 7562864.
  5. ^ Shamoian CA (1975). "Codeine and glutethimide. Euphoretic, addicting combination". New York State Journal of Medicine. 75 (1): 97–99. PMID 1053824.
  6. ^ Havier RG, Lin R (April 1985). "Deaths as a result of a combination of codeine and glutethimide". Journal of Forensic Sciences. 30 (2): 563–6. doi:10.1520/JFS11840J. PMID 3998703. S2CID 45780806.
  7. ^ a b Gahlinger P (2003). "Methaqualone and Glutethimide". Illegal Drugs: A Complete Guide to Their History, Chemistry, Use, and Abuse. ISBN 9780452285057. OCLC 52269170.
  8. ^ Popa D, Loghin F, Imre S, Curea E (August 2003). "The study of codeine-gluthetimide pharmacokinetic interaction in rats". Journal of Pharmaceutical and Biomedical Analysis. 32 (4–5): 867–77. doi:10.1016/s0731-7085(03)00189-4. PMID 12899973.
  9. ^ Khajawall AM, Sramek JJ, Simpson GM (August 1982). "'Loads' alert". The Western Journal of Medicine. 137 (2): 166–8. PMC 1274052. PMID 7135952.
  10. ^ "List of psychotropic substances under international control" (PDF). International Narcotics Control Board. Archived from the original (PDF) on 2012-08-31.
  11. ^ "Section 1308.12 Schedules of Controlled Substances". Title 21 Code of Federal Regulations. Drug Enforcement Administration. Archived from the original on 2015-08-04. Retrieved 2011-10-07.
  12. ^ Havier RG, Lin R (April 1985). "Deaths as a result of a combination of codeine and glutethimide". Journal of Forensic Sciences. 30 (2): 563–6. doi:10.1520/JFS11840J. PMID 3998703. S2CID 45780806.
  13. ^ Feuer E, French J (February 1984). "Descriptive epidemiology of mortality in New Jersey due to combinations of codeine and glutethimide". American Journal of Epidemiology. 119 (2): 202–7. doi:10.1093/oxfordjournals.aje.a113738. PMID 6695899.
  14. ^ Houlihan WJ, Bennett GB (January 1977). "Anti-Anxiety Agents, Anticonvulsants and Sedative-Hypnotics". Annual Reports in Medicinal Chemistry. 12. Academic Press: 10–19. doi:10.1016/S0065-7743(08)61540-7.
  15. ^ Tagmann E, Sury E, Hoffmann K (1952). "Über Alkylenimin-Derivate. 2. Mitteilung". Helvetica Chimica Acta. 35 (5): 1541–1548. doi:10.1002/hlca.19520350516.
  16. ^ Salmon-Legagneur F, Neveu C (January 1952). "Sur Les Acides Alpha-Phenyl Alpha-Alcoyl (Ou Phenoalcoyl) Glutariques". Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences. 234 (10): 1060–2.
  17. ^ Salmon-Legagneur F, Neveu C (1953). "Sur Les Acides Alpha-Phenyl Alpha-Alcoyl (Ou Phenoalcoyl) Glutariques". Bull. Soc. Chim. France: 70.
  18. ^ DE patent 950193, Hoffmann K Tagmann E, "Verfahren zur Herstellung neuer Dioxopiperidine", issued 4 October 1956, assigned to CIBA 
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