Phenmetrazine

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Phenmetrazine
Phenmetrazine.svg
Clinical data
Trade names Preludin, others
Routes of
administration 		By mouth, Intravenous, Vaporized, Insufflated, Suppository
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 8 hours
Excretion Kidney
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and many others) is a stimulant drug first synthesized in 1952 and originally used as an appetite suppressant, but withdrawn from the market in the 1980s due to widespread abuse.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

Phenmetrazine's 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. Formerly 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]

Related Research Articles

<span class="mw-page-title-main">Amphetamine</span> Central nervous system stimulant

Amphetamine is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity; it is also used to treat binge eating disorder in the form of its inactive prodrug lisdexamfetamine. 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">Methylphenidate</span> Central nervous system stimulant

Methylphenidate, sold under the brand names Ritalin and Concerta among others, is a central nervous system (CNS) stimulant used medically to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, narcolepsy. It is a first-line treatment for ADHD ); it may be taken by mouth or applied to the skin, and different formulations have varying durations of effect. For ADHD, the effectiveness of methylphenidate is comparable to atomoxetine but modestly lower than amphetamines, alleviating the executive functioning deficits of sustained attention, inhibition, working memory, reaction time and emotional self-regulation.

<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, sold under the brand name Bontril among others, is a stimulant medication of the morpholine chemical class used as an appetite suppressant.

<span class="mw-page-title-main">Levmetamfetamine</span> Topical nasal decongestant

Levmetamfetamine, also known as l-desoxyephedrine or levomethamphetamine, and commonly sold under the brand name Vicks VapoInhaler among others, is an optical isomer of methamphetamine primarily used as a topical nasal decongestant. It is used to treat nasal congestion from allergies and the common cold. It was first used medically as decongestant beginning in 1958 and has been used for such purposes, primarily in the United States, since then.

<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.

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

Aminorex is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension. 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.

<span class="mw-page-title-main">Dexamyl</span> Discontinued medication

Dexamyl was the brand name of a combination drug composed of amobarbital and dextroamphetamine (Dexedrine) within the same pill. It was widely abused and is no longer manufactured.

<span class="mw-page-title-main">Chlorphentermine</span> Weight loss medication

Chlorphentermine, sold under the brand names Apsedon, Desopimon, and Lucofen, is a serotonergic appetite suppressant of the amphetamine family. Developed in 1962, it is the para-chloro derivative of the better-known appetite suppressant phentermine, which is still in current use.

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

Etilamfetamine, also known as N-ethylamphetamine and formerly sold under the brand names Apetinil and Adiparthrol, is a stimulant drug of the amphetamine family. It was invented in the early 20th century and was subsequently used as an anorectic or appetite suppressant in the 1950s, but was not as commonly used as other amphetamines such as amphetamine, methamphetamine, and benzphetamine, and was largely discontinued once newer drugs such as phenmetrazine were introduced.

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

Naphthylaminopropane, also known as naphthylisopropylamine (NIPA), is an experimental drug that was under investigation for the treatment of alcohol and stimulant addiction.

<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.

Desbutal was a brand name drug by Abbott containing 5 mg methamphetamine hydrochloride (Desoxyn) and 30 mg pentobarbital sodium (Nembutal); a substituted amphetamine and a barbiturate combined within the same pill. Desbutal was marketed as an antidepressant as well as a medication for the treatment of obesity, narcolepsy, parkinsonism, and alcoholism, although it was commonly also prescribed off-label for miscellaneous ailments. It had a high abuse potential and is no longer manufactured.

<span class="mw-page-title-main">Norepinephrine releasing agent</span> Catecholaminergic type of drug

A norepinephrine releasing agent (NRA), also known as an adrenergic releasing agent, is a catecholaminergic type of drug that induces the release of norepinephrine (noradrenaline) and epinephrine (adrenaline) from the pre-synaptic neuron into the synapse. This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine therefore an increase in adrenergic neurotransmission.

<span class="mw-page-title-main">Dopamine releasing agent</span> Type of drug

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain.

<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

3-Fluorophenmetrazine is a phenylmorpholine-based stimulant and fluorinated analogue of phenmetrazine that has been sold online as a designer drug.

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

Substituted phenylmorpholines, or substituted phenmetrazines alternatively, are chemical derivatives of phenylmorpholine or of the psychostimulant drug phenmetrazine. Most such compounds act as releasers of monoamine neurotransmitters, and have stimulant effects. Some also act as agonists at serotonin receptors, and compounds with an N-propyl substitution act as dopamine receptor agonists. A number of derivatives from this class have been investigated for medical applications, such as for use as anorectics or medications for the treatment of ADHD. Some compounds have also become subject to illicit use as designer drugs.

<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.

References

  1. ↑ Anvisa (31 March 2023). "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 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  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 20 May 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 26 March 2017. Retrieved 5 May 2020.{{cite journal}}: CS1 maint: unfit URL (link)
  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 31 October 2009.
  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. US Government Printing Office. pp. 198–99.
  17. ↑ Dash L (1996). Rosa Lee. HarperCollins. p. 108.
  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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