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Phenmetrazine

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Phenmetrazine
Clinical data
Trade namesPreludin, 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 classNorepinephrine–dopamine releasing agent; Psychostimulant; Appetite suppressant
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Elimination half-life8 hours[citation needed]
ExcretionKidney[citation needed]
Identifiers
  • 3-methyl-2-phenylmorpholine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.004.677 Edit this at Wikidata
Chemical and physical data
FormulaC11H15NO
Molar mass177.247 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 checkY
  • Key:OOBHFESNSZDWIU-UHFFFAOYSA-N checkY
  (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among others, is a stimulant drug first synthesized in 1952 and originally used as an appetite suppressant, but withdrawn from the market in the 1980s due to widespread misuse.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.

Medical uses

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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

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Pharmacodynamics

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Phenmetrazine acts as a norepinephrine and dopamine releasing agent (NDRA), with EC50Tooltip 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 (EC50Tooltip Half maximal effective concentration, nM)
Compound NETooltip Norepinephrine DATooltip Dopamine 5-HTTooltip Serotonin Ref
Phenethylamine 10.9 39.5 >10,000 [11][12][8]
Dextroamphetamine 6.6–10.2 5.8–24.8 698–1,765 [13][14][8][15]
Dextromethamphetamine 12.3–14.3 8.5–40.4 736–1,292 [13][16][8][15]
2-Phenylmorpholine 79 86 20,260 [10]
Phenmetrazine 29–50.4 70–131 7,765–>10,000 [7][8][9][10]
Phendimetrazine >10,000 >10,000 >100,000 [7][8][15]
Pseudophenmetrazine 514 >10,000 (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]

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.[21]

Pharmacokinetics

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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.[22]

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

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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.[23] It is the (2RS,3RS)- or (±)-trans- enantiomer of 2-phenyl-3-methylmorpholine.[23]

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.[24]

Synthesis

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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]

History

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Phenmetrazine was first patented in Germany in 1952 by Boehringer-Ingelheim,[25][26] with some pharmacological data published in 1954.[27] It was the result of a search by Thomä and Wick for an anorectic drug without the side effects of amphetamine.[28] Phenmetrazine was introduced into clinical use in 1954 in Europe.[29]

Society and culture

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Names

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Phenmetrazine is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, and BANTooltip British Approved Name.[23][30][31] It is also known by the brand name Preludin.[23]

Availability

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In 2004, phenmetrazine remained marketed only in Israel.[31][30]

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Phenmetrazine is a Schedule II controlled substance in the United States.[32]

Recreational use

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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.[33] 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.[34] Hunter Davies asserted, in his 1968 biography of the band,[35] 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.[36]

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".[37] Phenmetrazine continues to be used and abused around the world, in countries including South Korea.[38]

References

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  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. ^ a b c "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.
  3. ^ a b c 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. The value of dexamphetamine 5 mg. b.d. and phenmetrazine 25 mg. b.d. in promoting weight loss in obese patients has been compared with that of an inert tablet. Phenmetrazine appeared to be slightly more effective than dexamphetamine, but both were more effective than the inert tablet.
  4. ^ a b c d Chait LD, Uhlenhuth EH, Johanson CE (1986). "The discriminative stimulus and subjective effects of d-amphetamine, phenmetrazine and fenfluramine in humans". Psychopharmacology (Berl). 89 (3): 301–306. doi:10.1007/BF00174364. PMID 3088654. The discriminative stimulus (DS) and subjective effects of d-amphetamine (AMP), phenmetrazine (PMT) and fenfluramine (FFL) were studied in a group of normal healthy adults. Subjects (N=27) were trained to discriminate between placebo and 10 mg AMP (PO). [...] Discriminators were tested with doses of PMT (25 and 50 rag) and FFL (20 and 40 mg) to determine whether the DS properties of these drugs would substitute for those of AMP. Both doses of PMT consistently substituted for AMP, and PMT produced subjective effects very similar to those of AMP. [...] PMT is an amphetamine-like anorectic which produces a profile of subjective states very similar to that of the amphetamines (Martin et al. 1971; Chait et al. 1984b) and which substitutes for AMP in drug discrimination studies in laboratory animals (Schuster and Johanson 1985).
  5. ^ a b c d Martin WR, Sloan JW, Sapira JD, Jasinski DR (1971). "Physiologic, subjective, and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man". Clin Pharmacol Ther. 12 (2): 245–258. doi:10.1002/cpt1971122part1245. PMID 5554941. Five centrally acting sympathomimetic amines, d-amphetamine, d-methamphetamine, ephedrine, phenmetrazine, and methylphenidate, were studied in man. All of these agents increased blood pressure and respiratory rate, produced similar types of subiective changes, and increased the excretion of epinephrine. [...] Aside from the fact that phenmetrazine was 1/3 to 1/4 as potent as either amphetamine or methamphetamine, it seemed to be qualitatively similar to amphetamine and methamphetamine.
  6. ^ a b c d 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.
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  8. ^ a b c d e f g h Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. OL 18589888W.
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  11. ^ a b c d Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, et al. (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug Alcohol Depend. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC 4297708. PMID 25548026. Phenmetrazine was a DA releasing anorectic therapeutic in the 1950s and early 1960s, sold under the name Predulin® (Rothman et al., 2002) but was removed from the clinic due to its addiction liability. It is a potent DA releaser with an EC50 of 87.4 nM (Table 5). However, phenmetrazine was found to be completely inactive at VMAT2 indicating that a direct interaction of the releaser with VMAT2 is not required for inducing neurotransmitter efflux into the extracellular space (Partilla et al., 2006). Phentermine and benzylpiperazine were also found in the same study to lack VMAT2 activity (Table 5). These compounds thus represent yet another atypical class of releaser.
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  16. ^ Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, et al. (April 2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC 3306880. PMID 22169943.
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  18. ^ a b c 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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  24. ^ Mayer FP, Burchardt NV, Decker AM, Partilla JS, Li Y, McLaughlin G, et al. (May 2018). "Fluorinated phenmetrazine "legal highs" act as substrates for high-affinity monoamine transporters of the SLC6 family". Neuropharmacology. 134 (Pt A): 149–157. doi:10.1016/j.neuropharm.2017.10.006. PMC 7294773. PMID 28988906.
  25. ^ GB 773780, Boehringer A, Boehringer E, "Improvements in or relating to the preparation of substituted morpholines" 
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  27. ^ 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.
  28. ^ Martel A (January 1957). "Preludin (phenmetrazine) in the treatment of obesity". Canadian Medical Association Journal. 76 (2): 117–120. PMC 1823494. PMID 13383418.
  29. ^ Kalant OJ (1966). The Amphetamines: Toxicity and Addiction. ISBN 0-398-02511-8.
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  33. ^ Brecher EM. "The Swedish Experience". Retrieved 31 October 2009.
  34. ^ Miles B (1998). Paul McCartney: Many Years from Now. H. Holt. pp. 66–67. ISBN 0-8050-5248-8.
  35. ^ Davies H (1968). The Beatles: The Authorized Biography. New York, McGraw-Hill Book Co. p. 78. ISBN 0-07-015457-0.
  36. ^ Ruby J (1964). Testimony of Jack Ruby. Vol. 5. US Government Printing Office. pp. 198–99.
  37. ^ Dash L (1996). Rosa Lee. HarperCollins. p. 108.
  38. ^ 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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