Glutethimide

Glutethimide (primarily branded Doriden) is a central nervous system (CNS) depressant drug and of the piperidine chemical class, one of many non-barbiturate tranquilizers produced in the twentieth century, albeit exhibiting barbiturate-like" effects caused by many GABAergics, used for its calming, relaxing, tranquilizing properties, in addition to relieving anxiety and promoting sleep.

Glutethimide

Clinical data
Pronunciation	/ɡluːˈtɛθɪˌmaɪd/ gloo-TE-thi-MYDE
Trade names	Doriden, Elrodorm, Noxyron, others
Pregnancy category	C: (United States)
Dependence liability	Moderate - high
Routes of administration	By mouth
ATC code	N05CE01 (WHO)
Legal status
Legal status	AU: S8 (Controlled drug) BR: Class B1 (Psychoactive drugs)[1] CA: Schedule IV DE: Anlage II (Authorized trade only, not prescriptible) UK: Class B US: Schedule II UN: Psychotropic Schedule III
Pharmacokinetic data
Bioavailability	Variable (Tmax = 1–6 hours)[2]
Protein binding	~50%
Metabolism	Extensive hepatic
Elimination half-life	8–12 hours
Excretion	Renal
Identifiers
IUPAC name 3-ethyl-3-phenyl-piperidine-2,6-dione
CAS Number	77-21-4 Y
PubChem CID	3487
IUPHAR/BPS	7192
DrugBank	DB01437 Y
ChemSpider	3367 Y
UNII	C8I4BVN78E
KEGG	D00532 Y
ChEMBL	ChEMBL1102 Y
CompTox Dashboard (EPA)	DTXSID1023102
ECHA InfoCard	100.000.921
Chemical and physical data
Formula	C13H15NO2
Molar mass	217.268 g·mol−1
3D model (JSmol)	Interactive image
Melting point	84 °C (183 °F)
Solubility in water	999 mg/L (30 °C/86 °F) mg/mL (20 °C)
SMILES O=C1NC(CCC1(CC)C2=CC=CC=C2)=O
InChI 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) Y Key:JMBQKKAJIKAWKF-UHFFFAOYSA-N Y
(verify)

History

Glutethimide was developed and released by Ciba Specialty Chemicals in 1954, and was approved by the Food and Drug Administration (FDA) for use in the United States in 1957 for treating insomnia, primarily under the brand name Doriden., while other trade names includedElrodorm and Noxyrom^[3] Generic formulations were marketed beginning in the early 1970s, which overlapped with the passage of the Controlled Substances Act, which marked the start of the American War on Drugs, shortly thereafter leading to increased scrutiny and regulation by the U.S. Drug Enforcement Agency, created in 1973 and highly focused on e was recognized as having a similar abuse potential, being as habit-forming and addicting as barbiturates and similar CNS depressants commonly used at the time (e.g. methaqualone, ethchlorvynol, meprobamate, and ethinamate. Abrupt cessation of this substance can result in rebound effects similar those found in alcohol withdrawal, as well from barbiturates and benzoediazpines, given their similar mechanism of action with regard to GABA.

Chemical Compoition and Synthesis

The (R) isomer has a faster onset of actionand more potent anticonvulsant activity in animal models than the (S) isomer.^[4]

Thieme Synthesis:^[5][6][7] Patent:^[8][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).

Mechanism of Action

Glutethimide is a CYP2D6 enzyme inducer, enabling the body to convert higher amounts of codeine to morphine, frequently leading to s users ingesting the substance with Tylenol 4 (codeine/acetaminophen).

Uses

Prescription

Doriden was commonly prescribed as a sleeping pill until the 1970s, when prescriptions gradually began to decline. Following long-term use, abrupt withdrawal of glutethimide was found to produce rebound effects resembling those of barbiturate withdrawal; anecdotally, patients consistently taking stable doses of the drug long-term have reported symptoms including delirium, hallucinosis, convulsions, and fever.^[9]

Recreational misuse

Glutethimide was often combined with products containing codeine, which metabolizes upon ingestion into morphine.colloquially called "hits," "pancakes and syrup," and most frequently "Dors and 4s", a highly potent and often lethal combination, resulting in fatal respiratory depression.^[10][11] In recreational quantities, any form of glutethimide was colloquially called a "Ciba" and all trade names of the medicine were manufactured as a pill/tablet directed to be taken by mouth. Each branded tablet was scored and white in color, and contained 500 mg of the active ingredient, which was prescribed to be used 1-2 times daily. Glutethimide was available in the United States until 1993, when production ceased and it was withdrawn from the market. Since 2013, the U.S. Drug Enforcement Administration has limited annual production to three grams, equivalent to six Doriden tablets, suggesting current use is limited to small-scale research.^{[citation needed]}

The drug became increasingly harder to access in the 1970s, increasing demand for glutethimide in such urban centers as Boston, Philadelphia, Pittsburgh, New York City, Baltimore, and Newark, New Jersey, leading to small-scale clandestine synthesis of glutethimide beginning in 1984, when methaqualone was fully withdrawan from the U.S. market and nearly impossible to access.^[12]: 203

Clinical Use and Research

Glutethimide's effect on quickening the conversion of codeine to morphine was 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, particularly as a Substitutionmittel that may be a useful alternative to methadone.^[13][14]

Discontinuation

Commercial production of glutethimide was discontinued in the U.S. in 1993, followed by several Eastern European countries in 2006, notably Hungary. Analysis of confiscated glutethimide seems to invariably show the drug or the results of attempted synthesis, as opposed to being "laced" with similar depressants.^[12]

Legal status

United States

Glutethimide is a Schedule II drug under the Convention on Psychotropic Substances.^[15] 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,^[16] several years after it was discovered that misuse combined with codeine increased the effect of the codeine and deaths had resulted from the combination.^[17][18] It has a DEA ACSCN of 2550 and a 2013 production quota of 3 g.

See also

• Aminoglutethimide, close relative to this substance
• Piperidione
• Methyprylon, sometimes spelled methyprylone and branded Noludar and Dimeran
• Pyrithyldione