Phenmetrazine

Last updated

Phenmetrazine
Phenmetrazine.svg
Clinical data
Trade names Preludin, others
Other namesFenmetrazine; Oxazimedrine; Phenmetrazin; 3-Methyl-2-phenylmorpholine; 2-Phenyl-3-methylmorpholine; 3-Methyl-2-phenyltetrahydro-2H-1,4-oxazine; PAL-55; PAL55; Prellies
Routes of
administration 		By mouth, Intravenous, Vaporized, Insufflated, Suppository
Drug class Norepinephrine–dopamine releasing agent; Psychostimulant; Appetite suppressant
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 8 hours[ citation needed ]
Excretion Kidney [ citation needed ]
Identifiers
  • 3-methyl-2-phenylmorpholine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
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
   (verify)

Phenmetrazine, sold under the brand name Preludin among others, is a stimulant drug first synthesized in 1952 and originally used as an appetite suppressant, but withdrawn from the market in the 1980s due to widespread misuse. 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 misuse and addiction. Chemically, phenmetrazine is a substituted amphetamine containing a morpholine ring or a substituted phenylmorpholine.

Contents

Medical uses

Phenmetrazine has been used as an appetite suppressant for purposes of weight loss. [2] It was used therapeutically for this indication at a dosage of 25 mg two or three times per day (or 50–75 mg/day total) in adults. [2] Phenmetrazine has been found to produce similar weight loss to dextroamphetamine in people with obesity. [3]

In addition to its appetite suppressant effects, phenmetrazine produces psychostimulant and sympathomimetic effects. [4] [5] [2] Phenmetrazine has been shown to produce very similar subjective psychostimulant effects to those of amphetamine and methamphetamine in clinical studies. [4] [5] Although able to produce comparable effects however, phenmetrazine has only about one-fifth to one-third of the potency of dextroamphetamine by weight. [5] [4] [3]

Pharmacology

Pharmacodynamics

Phenmetrazine acts as a norepinephrine and dopamine releasing agent (NDRA), with EC50 Tooltip half-maximal effective concentration values for induction of norepinephrine and dopamine release of 29–50 nM and 70–131 nM, respectively. [6] [7] [8] [9] [10] It has very weak activity as a releaser of serotonin, with an EC50 value of 7,765 to >10,000 nM. [6] [7] [8] [9] [10] The drug is several times less potent than dextroamphetamine and dextromethamphetamine as an NDRA in vitro . [6] [7] [8] [9] [10] This is in accordance with the higher doses required clinically. [5] [4] [3]

Monoamine release of phenmetrazine and related agents (EC50 Tooltip Half maximal effective concentration, nM)
Compound NE Tooltip Norepinephrine DA Tooltip Dopamine 5-HT Tooltip SerotoninRef
Phenethylamine 10.939.5>10,000 [11] [12] [8]
Dextroamphetamine 6.6–10.25.8–24.8698–1,765 [13] [14] [8] [15]
Dextromethamphetamine 12.3–14.38.5–40.4736–1,292 [13] [16] [8] [15]
2-Phenylmorpholine 798620,260 [10]
Phenmetrazine 29–50.470–1317,765–>10,000 [7] [8] [9] [10]
  (+)-Phenmetrazine37.587.43246 [7]
  (–)-Phenmetrazine62.9415>10,000 [7]
Phendimetrazine >10,000>10,000>100,000 [7] [8] [15]
Pseudophenmetrazine 514>10,000 (RI)>10,000 [7]
  (+)-Pseudophenmetrazine3491,457>10,000 [7]
  (–)-Pseudophenmetrazine2,511IA (RI)>10,000 [7]
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: [17] [6]

In contrast to many other monoamine releasing agents (MRAs), phenmetrazine is inactive in terms of vesicular monoamine transporter 2 (VMAT2) actions. [11] [18] A few other MRAs have also been found to be inactive at VMAT2, such as phentermine and benzylpiperazine (BZP). [11] [18] These findings indicate that VMAT2 activity is non-essential for robust MRA actions. [11] [18]

Phenmetrazine does not appear to have been assessed at the trace amine-associated receptor 1 (TAAR1). [19] [20]

Phenmetrazine has been found to dose-dependently elevate brain dopamine levels in rodents in vivo . [7] A 10 mg/kg i.v. dose of phenmetrazine increased nucleus accumbens dopamine levels by around 1,400% in rats. [7] For comparison, dextroamphetamine 3 mg/kg i.p. increased striatal dopamine levels by about 5,000% in rats. [21] On the other hand, the maximal increases in brain dopamine levels with phenmetrazine are similar to those with the proposed dopamine transporter (DAT) "inverse agonists" methylphenidate and cocaine (e.g., ~1,500%). [21] Dopamine-releasing drugs that lack VMAT2 activity are theorized to produce much smaller maximal impacts on dopamine levels under experimental conditions than those which also act on VMAT2 like amphetamine. [21] However, the pharmacological significance of these VMAT2 interactions in humans is unclear. [22]

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 four times as effective in both methods of administration. [23]

Pharmacokinetics

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. [24]

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.

Chemistry

Phenmetrazine, also known as (2RS,3RS)-2-phenyl-3-methylmorpholine or as (2RS,3RS)-3-methyl-2-phenyltetrahydro-2H-1,4-oxazine, is a substituted phenylmorpholine. [25] It is the (2RS,3RS)- or (±)-trans- enantiomer of 2-phenyl-3-methylmorpholine. [25]

Phenmetrazine's chemical structure incorporates the backbone of amphetamine, the prototypical psychostimulant 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 norepinephrine releasing agents.

A variety of phenmetrazine analogues and derivatives have been encountered as designer drugs. [26] In addition, the activities of various phenmetrazine analogues and derivatives as monoamine releasing agent (MRA) have been described. [7] [26] [10]

Synthesis

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. [10]

Phenmetrazine Synthesis.svg

History

Phenmetrazine was first patented in Germany in 1952 by Boehringer-Ingelheim, [27] [28] with some pharmacological data published in 1954. [29] It was the result of a search by Thomä and Wick for an anorectic drug without the side effects of amphetamine. [30] Phenmetrazine was introduced into clinical use in 1954 in Europe. [31]

Society and culture

Names

Phenmetrazine is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, and BAN Tooltip British Approved Name. [25] [32] [33] It is also known by the brand name Preludin. [25]

Availability

In 2004, phenmetrazine remained marketed only in Israel. [33] [32]

Phenmetrazine is a Schedule II controlled substance in the United States. [34]

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. [35] 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. [36] Hunter Davies asserted, in his 1968 biography of the band, [37] 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. [38]

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". [39] Phenmetrazine continues to be used and abused around the world, in countries including South Korea. [40]

Related Research Articles

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

Phentermine, sold under the brand name Adipex-P among others, is a medication used together with diet and exercise to treat obesity. It is available by itself or as the combination phentermine/topiramate. Phentermine is taken by mouth.

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

Aminorex, sold under the brand names Menocil and Apiquel among others, is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension (PPH). In the United States, aminorex is a Schedule I controlled substance.

<span class="mw-page-title-main">Vesicular monoamine transporter 2</span> Mammalian protein found in Homo sapiens

The solute carrier family 18 member 2 (SLC18A2) also known as vesicular monoamine transporter 2 (VMAT2) is a protein that in humans is encoded by the SLC18A2 gene. SLC18A2 is an integral membrane protein that transports monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles. In nigrostriatal pathway and mesolimbic pathway dopamine-releasing neurons, SLC18A2 function is also necessary for the vesicular release of the neurotransmitter GABA.

<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">Propylamphetamine</span> Chemical compound

Propylamphetamine is a psychostimulant of the amphetamine family which was never marketed. It was first developed in the 1970s, mainly for research into the metabolism of, and as a comparison tool to, other amphetamines.

<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">Norfenfluramine</span> Never-marketed drug of the amphetamine family

Norfenfluramine, or 3-trifluoromethylamphetamine, is a never-marketed drug of the amphetamine family and a major active metabolite of the appetite suppressants fenfluramine and benfluorex. The compound is a racemic mixture of two enantiomers with differing activities, dexnorfenfluramine and levonorfenfluramine.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters. The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; MRAs can induce the release of one or more of these neurotransmitters.

<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">4-Methylamphetamine</span> Stimulant and anorectic drug of the amphetamine class

4-Methylamphetamine (4-MA), also known by the former proposed brand name Aptrol, is a stimulant and anorectic drug of the amphetamine family. It is structurally related to mephedrone (4-methylmethcathinone).

<span class="mw-page-title-main">4-Methylmethamphetamine</span> Stimulant and entactogen drug of the amphetamine class

4-Methylmethamphetamine (4-MMA), also known as mephedrine, is a putative stimulant and entactogen drug of the amphetamine family. It acts as a serotonin–norepinephrine–dopamine releasing agent (SNDRA). The drug is the β-deketo analogue of mephedrone and the N-methyl analogue of 4-methylamphetamine (4-MA).

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

Pseudophenmetrazine is a psychostimulant of the phenylmorpholine group. 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.

<span class="mw-page-title-main">4,4'-Dimethylaminorex</span> Chemical compound

4,4'-Dimethylaminorex, sometimes referred to by the street name "Serotoni", is a psychostimulant and entactogen designer drug related to aminorex, 4-methylaminorex, and pemoline. It was first detected in the Netherlands in December 2012, and has been sold as a designer drug around Europe since mid-2013.

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

Methamnetamine is a triple monoamine releasing agent and N-methyl analog of the non-neurotoxic experimental drug naphthylaminopropane and the naphthalene analog of methamphetamine. It has been sold online as a designer drug.

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

3',4'-Methylenedioxy-4-methylaminorex (MDMAR) is a recreational designer drug from the substituted aminorex family, with monoamine-releasing effects. It is a potent serotonin–norepinephrine–dopamine releasing agent (SNDRA).

<span class="mw-page-title-main">BMAPN</span> Substituted cathinone stimulant drug

BMAPN, also known as βk-methamnetamine or as 2-naphthylmethcathinone, is a substituted cathinone derivative with stimulant effects. It inhibits dopamine reuptake and has rewarding and reinforcing properties in animal studies. It is banned under drug analogue legislation in a number of jurisdictions. The drug was at one point marketed under the name NRG-3, although only a minority of samples of substances sold under this name have been found to actually contain BMAPN, with most such samples containing mixtures of other cathinone derivatives.

<span class="mw-page-title-main">Butylamphetamine</span> Amphetamine derivative and stimulant

Butylamphetamine is a psychostimulant of the substituted amphetamine family which was never marketed.

<span class="mw-page-title-main">2-Phenylmorpholine</span> Pharmaceutical compound

2-Phenylmorpholine is the parent compound of the substituted phenylmorpholine class of compounds. Examples of 2-phenylmorpholine derivatives include phenmetrazine (3-methyl-2-phenylmorpholine), phendimetrazine ( -3,4-dimethyl-2-phenylmorpholine), and pseudophenmetrazine ( -3-methyl-2-phenylmorpholine), which are monoamine releasing agents (MRAs) and psychostimulants. 2-Phenylmorpholine itself is a potent norepinephrine–dopamine releasing agent (NDRA) and hence may act as a stimulant similarly.

<span class="mw-page-title-main">Ethylnaphthylaminopropane</span> Pharmaceutical compound

Ethylnaphthylaminopropane is a monoamine releasing agent (MRA) of the amphetamine family that is related to naphthylaminopropane and methamnetamine. It acts specifically as a serotonin–norepinephrine–dopamine releasing agent (SNDRA). However, ENAP is unusual in being a partial releaser of serotonin and dopamine and a full releaser of norepinephrine.

<span class="mw-page-title-main">Naphthylmetrazine</span> Pharmaceutical compound

Naphthylmetrazine, also known as 3-methyl-2-(2′-naphthyl)morpholine, is a monoamine releasing agent (MRA) and monoamine reuptake inhibitor (MRI) of the phenylmorpholine family related to phenmetrazine. It is the analogue of phenmetrazine in which the phenyl ring has been replaced with a naphthalene ring.

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. 1 2 3 "Council on Pharmacy and Chemistry: New and Nonofficial Remedies: Phenmetrazine Hydrochloride". Journal of the American Medical Association. 163 (5): 357. 2 February 1957. doi:10.1001/jama.1957.02970400028010. ISSN   0002-9955. PMID   13385162.
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  10. 1 2 3 4 5 6 7 "Phenylmorpholines and analogues thereof". Google Patents. 20 May 2011. Retrieved 7 December 2024. [...] Table 3. Monoamine Release and 5HT2B Activity ofa Series of Phenmetrazine Analogs [...] Table 4. Comparison of the DA, 5-HT, and NE Releasing Activity of a Series of Phenmetrazine Analogs [...] Table 5. Comparison of the DA, 5-HT, and NE Releasing Activity of a Series of (2S,5S)-5-methyl-2-phenylmorpolines
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  18. 1 2 3 Partilla JS, Dempsey AG, Nagpal AS, Blough BE, Baumann MH, Rothman RB (October 2006). "Interaction of amphetamines and related compounds at the vesicular monoamine transporter". J Pharmacol Exp Ther. 319 (1): 237–246. doi:10.1124/jpet.106.103622. PMID   16835371. A number of test drugs displayed no activity in the [3H]dopamine uptake inhibition assay (Table 1). For example, (+)- phenmetrazine and (–)-phenmetrazine, the major metabolites of phendimetrazine (Rothman et al., 2002), were essentially inactive. [...] In contrast, other amphetaminetype agents, such as phentermine, phenmetrazine, and 1-benzylpiperazine, are potent releasers of neuronal dopamine (Baumann et al., 2000, 2005; Rothman et al., 2002), but they are inactive at VMAT2. Agents such as these may prove to be valuable control compounds for determining the importance of vesicular release for the in vivo actions of amphetamine-type agents.
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  21. 1 2 3 Heal DJ, Gosden J, Smith SL (December 2014). "Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine". Neuropharmacology. 87: 19–40. doi:10.1016/j.neuropharm.2014.06.012. PMID   24953830. The pharmacodynamics of the effect of cocaine on dopamine efflux from the nerve terminal would be similar to reverse transport of dopamine caused by competitive DAT substrate releasing agents. Because unlike the DAT substrates, cocaine has an extra-neuronal site of action, it is not able to evoke release of dopamine from the vesicular storage pool. This may explain why the maximum effect of competitive DAT substrate releasing agents on dopamine efflux is greater than that of DAT "inverse agonists". [...] Cocaine and related DAT "inverse agonists" are too large to serve as DAT substrates, and consequently, they cannot mobilise dopamine which is contained within the vesicular storage pool. This factor may explain why the DAT "inverse agonists" can compete with the DAT substrates in terms of speed of dopamine release, but the maximum size of their effect will always be smaller than that of the competitive DAT substrate releasing agents because of their inability to augment cytosolic dopamine with neurotransmitter displaced from the vesicular storage pool.
  22. ↑ Reith ME, Gnegy ME (2020). "Molecular Mechanisms of Amphetamines" (PDF). Handb Exp Pharmacol. 258: 265–297. doi:10.1007/164_2019_251. PMID   31286212. At lower doses, amphetamine preferentially releases a newly-synthesized pool of DA. [...] DA stores will not be depleted by the AMPT in these short time frames, leading to the conclusion that newly-synthesized DA is a principal substrate for amphetaminestimulated DA efflux. [...] Controversy has surrounded the role of VMAT2 and synaptic vesicles in the mechanism of amphetamine action. [...] Undoubtedly vesicles contribute strongly to the maximal DA released by amphetamine, although VMAT2 is not absolutely required for amphetamine to release DA from nerve terminals (Pifl et al., 1995; Fon et al., 1997; Wang et al., 1997; Patel et al., 2003). [...] more work is needed to fully reconcile this role of vesicular re-distributed DA serving as substrate for reverse transport by DAT with older results pointing to a preferential role of newly synthesized DA for amphetamine-induced release.
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  34. ↑ Bray GA, Purnell JQ (10 July 2022). "An Historical Review of Steps and Missteps in the Discovery of Anti-Obesity Drugs". MDText.com, Inc. PMID   35834619 . Retrieved 10 January 2025.
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