Methaqualone

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Structural formula
Structure of methaqualone
General
Non-proprietary name Methaqualone
other names
  • 2-methyl-3- (2-methylphenyl) -4 (3 H ) -quinazolinone
  • 2-methyl-3- ( o -tolyl) -4-quinazolone
Molecular formula C 16 H 14 N 2 O
External identifiers / databases
CAS number
EC number 200-780-4
ECHA InfoCard 100,000.710
PubChem 6292
ChemSpider 6055
DrugBank DB04833
Wikidata Q423912
Drug information
ATC code

N05 CM01

Drug class

Hypnotic

properties
Molar mass 250.30 g mol −1
Melting point
  • 120 ° C
  • 255–256 ° C (hydrochloride)
pK s value

2.54

solubility

heavy in water (4.73 g l −1 at 25 ° C)

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
06 - Toxic or very toxic

danger

H and P phrases H: 301
P: 301 + 310
Toxicological data

185 mg kg −1 ( LD 50 ,  rat ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Methaqualon , colloquially also called Quaaludes or Ludes , is a quinazoline derivative, the name of which is derived from the English chemical name Meth yl qu in a zo l in on e (German: Methylquinazolinon). It is a drug that was used as a hypnotic and an intoxicant, and is still in use, currently in Africa.

history

It was discovered by chance in 1951 by the Indian researcher ML Gujiral while searching for an antimalarial drug and has been used as a sleep aid since the 1960s . In 1965 it was introduced in the USA under the trade names Quaalude ® and Parest ® as an alternative to the not harmless barbiturates . The drug originally advertised as non-addictive did lead to cases of physical and psychological dependence , which were reported in Great Britain as early as 1966.

As an intoxicant traded on the street , it soon became very popular in the USA due to its euphoric and aphrodisiac effects. In the early 1970s, the so-called " luding out ", the ingestion of 300 to 450 mg methaqualone with wine, was widespread among college students. The alcohol creates the feeling of indestructibility and strong euphoria triggered by methaqualone . Methaqualone lowers (like other sedative hypnotics ) the inhibition threshold and can thus lead to an increase in sexual perception.

In July 2015, court records from 2005 revealed that Bill Cosby was alleged to have administered narcotics to a woman in order to have sex without her knowledge in at least one case. He confirmed in a court case that he had used "Quaaludes" in this case.

pharmacology

Pharmacodynamics

Methaqualon is a positive allosteric modulator at GABA A receptors , namely at those types which are composed of the subunits α1,2,3,5 and β2,3 as well as γ2S. In addition, methaqualone behaves in type α4β1δ as a silent modulator, on α6β1δ as negative, on α4β2δ and α6β2,3δ as positive modulator, on α4β3δ as a “superagonist”. It has no effect on benzodiazepine, barbiturate or neurosteroid binding sites. It is assumed that a possible effective cavity is located in the transmembrane section of the interface β (+) α (-) and overlaps that of the anesthetic etomidate . As far as we know today (2015), it is considered a selective GABA A receptor ligand.

Pharmacokinetics and metabolism

The therapeutic plasma concentration is in the range from 0.4 to 5 μg / mL, the plasma half-life is 20 to 60 hours, and protein binding is given as 75–95%. Methaqualone is largely metabolized , primarily through hydroxylation on the methyl groups and the aromatic rings. Conjugation to O - glucuronides and O - methyl ethers follows . By N -oxidation to form Methaqualon- N oxide . Clear interindividual differences were observed in the proportion of the metabolites. 4'- and 2'-hydroxymethaqualone can be identified as the metabolites with the highest concentrations, followed by 3'-, 2- and 6-hydroxymethaqualone. The methaqualone molecule is sterically hindered and is subject to atropisomerism under physiological conditions . It is therefore chiral and corresponding rotamers exist. After administration of racemic methaqualone, 4'-hydroxymethaqualone is excreted almost stereospecifically in human urine . In the case of the 3'-, 2'- and 2-hydroxymetabolites, unequal enantiomeric ratios are observed, 6-hydroxymethaqualone is eliminated as a racemate. The enzymes CYP2D6 and CYP2C19 are not significantly involved in the metabolism.

Pharmaceutical status

In the USA, the drug was withdrawn from the market in 1984 due to its widespread use as an intoxicant, but it was still illegally produced, although the allegedly illegally produced methaqualone tablets that were later seized were mostly only high-dose benzodiazepines such as diazepam .

In the Federal Republic of Germany, methaqualone was on the market as a Normi-Nox , but was already subject to the Narcotics Act in 1981 and was therefore no longer prescribable as a substance listed in Annex II of the BtMG . Something similar happened to the active ingredient in the GDR, where methaqualone was the main component of the sleeping pill Dormutil , which was finally withdrawn from medical circulation due to its frequent use for intoxication purposes (the successor preparation known today as Dormutil N contains the active ingredient diphenhydramine ).

In Austria methaqualone was completely withdrawn because of its addictive potential in 1992, in Germany in 1993 its approval as a sleeping aid, while in Switzerland it remained widespread under the name Toquilone . However, it was only available as Toquilone compositum, which also contains diphenhydramine , and has not been available for prescription in Switzerland since 2005.

distribution

While methaqualone hardly plays a role as an intoxicant in western countries , it is widespread in some African countries, especially in South Africa . In South Africa, alongside marijuana, it is the most widespread illegal intoxicant (as of 2017), it comes on the black market in many different tablets, which, similar to the ecstasy tablets in this country , have different logos. Most of the methaqualone consumed there comes from illegal production from India , from where it is smuggled into Africa. The most common form of consumption there is smoking the crumbled tablets, often mixed with marijuana, which triggers a brief, very intense "euphoria flash". Then the sedative component begins to predominate and the consumer falls into a longer-lasting twilight state.

Historically, methaqualone is one of the sleeping pills that was used in the 1960s to replace the barbiturates, which were controversial due to a possible fatal overdose. Other examples are ethchlorvynol (trade name Placidyl) or glutethimide (trade name Doriden ). However, many of these substances caused euphoria and thus the risk of psychological dependence, which is why they are hardly used today. In some cases, they can also cause physical dependence. Interestingly, in experiments with methaqualone, the benzodiazepines were more or less accidentally discovered, which today meet almost all of the needs for sleeping pills and tranquilizers.

Side effects and addiction

Chronic use can lead to polyneuropathy , psychological and physical dependence . When taken in smaller doses, the effects can be euphoric instead of sedating, as would be expected with a sleeping pill. Possible symptoms of a methaqualone overdose are gastrointestinal complaints, drowsiness, ataxia , tingling, slow, slurred speech and muscle hyperactivity, internal bleeding, convulsions , coma .

Quaalude / Mandrax tablets and capsules

Scene names and representation in art

In drug slang, methaqualone is sometimes known as seven-one-fours , seventeen , or lemmon 714 . These names are all derived from the Lemmon 714 imprint on the Quaalude tablet. Other names are ludes (also from Quaalude) or simply Mandrax after the trade name of the same name. It was from under the trade name Mozambin Falco in Ganz Wien sung. Because of the size of the tablets, methaqualone was also known as " Gorilla Biscuits " in New York in the early 1980s , from which the straight edge band Gorilla Biscuits got their name. They are also mentioned and consumed several times in the film The Wolf of Wall Street (2013), whereby the side effects are also shown.

The effects and undesirable side effects described here were described by the singer-songwriter Shel Silverstein in his satirical song Quaaludes Again in 1980 . It is also mentioned in David Bowie's song Time : "... Quaaludes and red wine ..."

synthesis

Methaqualone can be synthesized by the condensation reaction of N- acetylanthranilic acid with o -toluidine in toluene in the presence of a dehydrating reagent such as phosphoryl chloride . For this reason, anthranilic acid is subject to basic substance monitoring .

literature

Web links

Individual evidence

  1. ↑ a b c Entry on methaqualone in the ChemIDplus database of the United States National Library of Medicine (NLM) .
  2. ↑ a b c d e f Entry on methaqualone. In: Römpp Online . Georg Thieme Verlag, accessed on July 15, 2019.
  3. ↑ a b Datasheet Methaqualone hydrochloride from Sigma-Aldrich , accessed on October 22, 2016 ( PDF ).
  4. ↑ Etienne F. van Zyl: A survey of reported synthesis of methaqualone and some positional and structural isomers . In: Forensic Science International 122 (2001), pp. 142-149, doi: 10.1016 / S0379-0738 (01) 00484-4 .
  5. ↑ New Revelations Bill Cosby made women compliant with drugs . In: Frankfurter Allgemeine Zeitung . July 7, 2015 ( faz.net [accessed July 7, 2015]).
  6. ^ Sedatives: Bill Cosby made women docile with drugs. In: Zeit Online . July 7, 2015, accessed March 2, 2017 .
  7. ↑ Hammer H, Bader BM, Ehnert C, Bundgaard C, Bunch L, Hoestgaard-Jensen K, Schroeder OH, Bastlund JF, Gramowski-Voß A, Jensen AA: A Multifaceted GABAA Receptor Modulator: Functional Properties and Mechanism of Action of the Sedative -Hypnotic and Recreational Drug Methaqualone (Quaalude) . In: Molecular Pharmacology . 88, No. 2, 2015, pp. 401-20. doi : 10.1124 / mol.115.099291 . PMID 26056160 .
  8. ↑ a b Prost F, Thormann W: Enantiomeric analysis of the five major monohydroxylated metabolites of methaqualone in human urine by chiral capillary electrophoresis . In: Electrophoresis . 22, No. 15, 2001, pp. 3270-3280. doi : 10.1002 / 1522-2683 (200109) 22:15 <3270 :: AID-ELPS3270> 3.0.CO; 2-K . PMID 11589290 . More references there.
  9. ^ Prost F, Thormann W: Assessment of the stereoselective metabolism of methaqualone in man by capillary electrophoresis . In: Electrophoresis . 24, No. 15, 2003, pp. 2598-607. doi : 10.1002 / elps.200305512 . PMID 12900872 .
  10. ↑ Autobiography “Confessions” | Nina Hagen's wild life , last accessed on January 13, 2014.
  11. ↑ Patent GB843073 : 2-methyl-3-orthotolyl-4-quinazolone and acid addition salts thereof. Published August 4, 1960 Applicant: Laboratoires Toraude. ‌