Phenmetrazine

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Phenmetrazine
Phenmetrazine.svg
Clinical data
Routes of
administration 		Oral, Intravenous, Vaporized, Insufflated, Suppository
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 8 hours
Excretion Renal
Identifiers
  • 3-methyl-2-phenylmorpholine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.004.677 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C11H15NO
Molar mass 177.247 g·mol−1
3D model (JSmol)
  • CC1C(C2=CC=CC=C2)OCCN1
  • InChI=1S/C11H15NO/c1-9-11(13-8-7-12-9)10-5-3-2-4-6-10/h2-6,9,11-12H,7-8H2,1H3 Yes check.svgY
  • Key:OOBHFESNSZDWIU-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Phenmetrazine (INN, USAN, BAN) (brand name Preludin, and many others) is a stimulant drug first synthesized in 1952 and originally used as an appetite suppressant, but withdrawn from the market in the 1980s due to widespread abuse. It was initially replaced by its analogue phendimetrazine (under the brand name Prelu-2) which functions as a prodrug to phenmetrazine, but now it is rarely prescribed, due to concerns of abuse and addiction. Chemically, phenmetrazine is a substituted amphetamine containing a morpholine ring.

Contents

History

Phenmetrazine was first patented in Germany in 1952 by Boehringer-Ingelheim, [2] [3] with some pharmacological data published in 1954. [4] It was the result of a search by Thomä and Wick for an anorectic drug without the side-effects of amphetamine. [5] Phenmetrazine was introduced into clinical use in 1954 in Europe. [6]

Medical use

In clinical use, phenmetrazine produces less nervousness, hyperexcitability, euphoria and insomnia than drugs of the amphetamine family. [7] It tends not to increase heart rate as much as other stimulants. Due to the relative lack of side effects, one study found it well tolerated in children. [5] In a study of the effectiveness on weight loss between phenmetrazine and dextroamphetamine, phenmetrazine was found to be slightly more effective. [8]

Pharmacology

Phenmetrazine acts as a releasing agent of norepinephrine and dopamine with EC50 values of 50.4 ± 5.4 nM and 131 ± 11 nM, respectively. [9] It has negligible efficacy as a releaser of serotonin, with an EC50 value of only 7,765 ± 610 nM. [9]

After an oral dose, about 70% of the drug is excreted from the body within 24 hours. About 19% of that is excreted as the unmetabolised drug and the rest as various metabolites. [10]

In trials performed on rats, it has been found that after subcutaneous administration of phenmetrazine, both optical isomers are equally effective in reducing food intake, but in oral administration the levo isomer is more effective. In terms of central stimulation however, the dextro isomer is about 4 times as effective in both methods of administration. [11]

The salt which has been used for immediate-release formulations is phenmetrazine hydrochloride (Preludin). Sustained-release formulations were available as resin-bound, rather than soluble, salts. Both of these dosage forms share a similar bioavailability as well as time to peak onset, however, sustained-release formulations offer improved pharmacokinetics with a steady release of active ingredient which results in a lower peak concentration in blood plasma.

Synthesis

Phenmetrazine Synthesis.svg

Phenmetrazine can be synthesized in three steps from 2-bromopropiophenone and ethanolamine. The intermediate alcohol 3-methyl-2-phenylmorpholin-2-ol (1) is converted to a fumarate salt (2) with fumaric acid, then reduced with sodium borohydride to give phenmetrazine free base (3). The free base can be converted to the fumarate salt (4) by reaction with fumaric acid. [12]

Chemistry

Its structure incorporates the backbone of amphetamine, the prototypical CNS stimulant which, like phenmetrazine, is a releasing agent of dopamine and norepinephrine. The molecule also loosely resembles ethcathinone, the active metabolite of popular anorectic amfepramone (diethylpropion). Unlike phenmetrazine, ethcathinone (and therefore amfepramone as well) are mostly selective as noradrenaline releasing agents.

Recreational use

Phenmetrazine has been used recreationally in many countries, including Sweden. When stimulant use first became prevalent in Sweden in the 1950s, phenmetrazine was preferred to amphetamine and methamphetamine by users. [13] In the autobiographical novel Rush by Kim Wozencraft, intravenous phenmetrazine is described as the most euphoric and pro-sexual of the stimulants the author used.

Phenmetrazine was classified as a narcotic in Sweden in 1959, and was taken completely off the market in 1965. At first the illegal demand was satisfied by smuggling from Germany, and later Spain and Italy. At first, Preludin tablets were smuggled, but soon the smugglers started bringing in raw phenmetrazine powder. Eventually amphetamine became the dominant stimulant of abuse because of its greater availability.

Phenmetrazine was taken by the Beatles early in their career. Paul McCartney was one known user. McCartney's introduction to drugs started in Hamburg, Germany. The Beatles had to play for hours, and they were often given the drug (referred to as Prellies) by the maid who cleaned their housing arrangements, German customers, or by Astrid Kirchherr (whose mother bought them). McCartney would usually take one, but John Lennon would often take four or five. [14] Hunter Davies asserted, in his 1968 biography of the band, [15] that their use of such stimulants then was in response to their need to stay awake and keep working, rather than a simple desire for kicks.

Jack Ruby said he was on phenmetrazine at the time he killed Lee Harvey Oswald. [16]

Preludin was also used recreationally in the US throughout the 1960s and 1970s. It could be crushed up in water, heated and injected. The street name for the drug in Washington, DC was "Bam". [17] Phenmetrazine continues to be used and abused around the world, in countries including South Korea. [18]

See also

Related Research Articles

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Amphetamine is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s. It exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.

<span class="mw-page-title-main">Stimulant</span> Overarching term covers many drugs that increase activity of the central nervous system

Stimulants is an overarching term that covers many drugs including those that increase the activity of the central nervous system and the body, drugs that are pleasurable and invigorating, or drugs that have sympathomimetic effects. Stimulants are widely used throughout the world as prescription medicines as well as without a prescription as performance-enhancing or recreational drugs. Among narcotics, stimulants produce a noticeable crash or comedown at the end of their effects. The most frequently prescribed stimulants as of 2013 were lisdexamfetamine (Vyvanse), methylphenidate (Ritalin), and amphetamine (Adderall). It was estimated in 2015 that the percentage of the world population that had used cocaine during a year was 0.4%. For the category "amphetamines and prescription stimulants" the value was 0.7%, and for MDMA 0.4%.

<span class="mw-page-title-main">Sympathomimetic drug</span> Substance that mimics effects of catecholamines

Sympathomimetic drugs are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in heart rate, force of cardiac contraction, and blood pressure. The primary endogenous agonists of the sympathetic nervous system are the catecholamines, which function as both neurotransmitters and hormones. Sympathomimetic drugs are used to treat cardiac arrest and low blood pressure, or even delay premature labor, among other things.

<span class="mw-page-title-main">Phendimetrazine</span> Pharmaceutical drug

Phendimetrazine is a stimulant drug of the morpholine chemical class used as an appetite suppressant.

<span class="mw-page-title-main">4-Methylaminorex</span> Group of stereoisomers

4-Methylaminorex is a stimulant drug of the 2-amino-5-aryloxazoline class that was first synthesized in 1960 by McNeil Laboratories. It is also known by its street name "U4Euh" ("Euphoria"). It is banned in many countries as a stimulant.

<span class="mw-page-title-main">Amfepramone</span> Stimulant drug used as an appetite suppressant

Amfepramone, also known as diethylpropion, is a stimulant drug of the phenethylamine, amphetamine, and cathinone classes that is used as an appetite suppressant. It is used in the short-term management of obesity, along with dietary and lifestyle changes. Amfepramone has a similar chemical structure to the antidepressant and smoking cessation aid bupropion, which has also been developed as a weight-loss medicine when in a combination product with naltrexone.

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<span class="mw-page-title-main">Etilamfetamine</span> Chemical compound

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<span class="mw-page-title-main">Ethcathinone</span> Simulant designer drug

Ethcathinone, also known as ethylpropion or ETH-CAT, is a stimulant drug of the phenethylamine, amphetamine, and cathinone chemical classes. It is an active metabolite of the prodrug diethylcathinone and is fully responsible for its effects. Ethcathinone has been identified as an ingredient in both quasi-legal "party pills", and, along with mephedrone, has also been reported as having been sold as "ecstasy" in the Australian city of Cairns.

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Substituted amphetamines are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with substituents. The compounds in this class span a variety of pharmacological subclasses, including stimulants, empathogens, and hallucinogens, among others. Examples of substituted amphetamines are amphetamine (itself), methamphetamine, ephedrine, cathinone, phentermine, mephentermine, tranylcypromine, bupropion, methoxyphenamine, selegiline, amfepramone (diethylpropion), pyrovalerone, MDMA (ecstasy), and DOM (STP).

<span class="mw-page-title-main">Fenbutrazate</span> Chemical compound

Fenbutrazate (INN), also known as phenbutrazate (BAN), is a psychostimulant used as an appetite suppressant under the trade names Cafilon, Filon, and Sabacid in Europe, Japan, and Hong Kong. It is a derivative of phenmetrazine and may function as a prodrug due to its similarity to phendimetrazine.

<span class="mw-page-title-main">G-130</span> Chemical compound

G-130 is a drug with stimulant and anorectic effects, related to phenmetrazine.

<span class="mw-page-title-main">Pseudophenmetrazine</span> Chemical compound

Pseudophenmetrazine is a psychostimulant compound of the morpholine class. It is the N-demethylated and cis-configured analogue of phendimetrazine as well as the cis-configured stereoisomer of phenmetrazine. In addition, along with phenmetrazine, it is believed to be one of the active metabolites of phendimetrazine, which itself is inactive and behaves merely as a prodrug. Relative to phenmetrazine, pseudophenmetrazine is of fairly low potency, acting as a modest releasing agent of norepinephrine (EC50 = 514 nM), while its (+)-enantiomer is a weak releaser of dopamine (EC50 = 1,457 nM) whereas its (−)-enantiomer is a weak reuptake inhibitor of dopamine (Ki = 2,691 nM); together as a racemic mixture with the two enantiomers combined, pseudophenmetrazine behaves overall more as a dopamine reuptake inhibitor (Ki = 2,630 nM), possibly due to the (+)-enantiomer blocking the uptake of the (−)-enantiomer into dopaminergic neurons and thus preventing it from inducing dopamine release. Neither enantiomer has any significant effect on serotonin reuptake or release (both Ki = >10,000 nM and EC50 = >10,000 nM, respectively).

<span class="mw-page-title-main">3-Fluorophenmetrazine</span> Stimulant designer drug

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<span class="mw-page-title-main">Substituted phenylmorpholine</span> Class of chemical compounds

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<span class="mw-page-title-main">PDM-35</span> Chemical compound

2-Phenyl-3,5-dimethylmorpholine is a drug with stimulant and anorectic effects, related to phenmetrazine. Based on what is known from other phenylmorpholines with similar structure, it likely acts as a norepinephrine-dopamine releasing agent and may produce effects similar or slightly different to phenmetrazine.

<span class="mw-page-title-main">4-Methylphenmetrazine</span> Stimulant designer drug

4-Methylphenmetrazine is a recreational designer drug with stimulant effects. It is a substituted phenylmorpholine derivative, closely related to better known drugs such as phenmetrazine and 3-fluorophenmetrazine. It was first identified in Slovenia in 2015, and has been shown to act as a monoamine releaser with some preference for serotonin release.

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. ↑ GB 773780,Boehringer A, Boehringer E,"Improvements in or relating to the preparation of substituted morpholines"
  3. ↑ USpatent 2835669,Thomä O,"Process for the Production of Substituted Morpholines",issued May 20, 1958, assigned to C. H. Boehringer Sohn
  4. ↑ Thomä O, Wick H (1954). "Über einige Tetrahydro-1,4-oxazine mit sympathicomimetischen Eigenschaften". Arch. Exp. Pathol. Pharmakol. 222 (6): 540. doi:10.1007/BF00246905. S2CID   25143525.
  5. 1 2 Martel A (January 1957). "Preludin (phenmetrazine) in the treatment of obesity". Canadian Medical Association Journal. 76 (2): 117–120. PMC   1823494 . PMID   13383418.
  6. ↑ Kalant OJ (1966). The Amphetamines: Toxicity and Addiction. ISBN   0-398-02511-8.
  7. ↑ "PHENMETRAZINE hydrochloride". Journal of the American Medical Association. 163 (5): 357. February 1957. PMID   13385162.
  8. ↑ Hampson J, Loraine JA, Strong JA (June 1960). "Phenmetrazine and dexamphetamine in the management of obesity". Lancet. 1 (7137): 1265–1267. doi:10.1016/S0140-6736(60)92250-9. PMID   14399386.
  9. 1 2 Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID   17017961. Archived from the original on 2017-03-26. Retrieved 2020-05-05.
  10. ↑ Moffat AC, Osselton MD, Widdop D (2004). Clarke's Analysis of Drugs and Poisons. ISBN   0-85369-473-7.
  11. ↑ Engelhardt A (1961). "Studies of the Mechanism of the Anti-Appetite Action of Phenmetrazine". Biochem. Pharmacol. 8 (1): 100. doi:10.1016/0006-2952(61)90520-2.
  12. ↑ WO 2011146850,Blough BE, Rothman R, Landavazo A, Page KM, Decker AM,"Phenylmorpholines and analogues thereof", assigned to Research Triangle Institute, pages 51,54–55
  13. ↑ Brecher EM. "The Swedish Experience" . Retrieved 2009-10-31.
  14. ↑ Miles B (1998). Paul McCartney: Many Years from Now . H. Holt. pp.  66–67. ISBN   0-8050-5248-8.
  15. ↑ Davies H (1968). The Beatles: The Authorized Biography . New York, McGraw-Hill Book Co. p.  78. ISBN   0-07-015457-0.
  16. ↑ Ruby J (1964). Testimony of Jack Ruby. Vol. 5. Washington: US Government Printing Office. pp. 198–99.
  17. ↑ Dash L (1996). Rosa Lee. HarperCollins. p. 109.
  18. ↑ Choi H, Baeck S, Jang M, Lee S, Choi H, Chung H (February 2012). "Simultaneous analysis of psychotropic phenylalkylamines in oral fluid by GC-MS with automated SPE and its application to legal cases". Forensic Science International. 215 (1–3): 81–87. doi:10.1016/j.forsciint.2011.02.011. PMID   21377815.
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