Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Phenmetrazine: Difference between pages

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| tradename = Preludin, others

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| legal_BR = A3

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>

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| IUPAC_name = 3-methyl-2-phenylmorpholine

| C=11 | H=15 | N=1 | O=1

| SMILES = CC1C(C2=CC=CC=C2)OCCN1

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'''Phenmetrazine''' ([[International Nonproprietary Name|INN]], [[United States Adopted Name|USAN]], [[British Approved Name|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others) is a [[stimulant]] [[drug]] first synthesized in 1952 and originally used as an [[appetite suppressant]], but withdrawn from the market in the 1980s due to widespread [[drug abuse|abuse]]. It was initially replaced by its [[Structural analog|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 [[drug addiction|addiction]]. Chemically, phenmetrazine is a [[substituted amphetamine]] containing a [[morpholine]] ring.

== History ==

Phenmetrazine was first patented in [[Germany]] in 1952 by [[Boehringer-Ingelheim]],<ref>{{cite patent | inventor = Boehringer A, Boehringer E | title= Improvements in or relating to the preparation of substituted morpholines | country = GB | number= 773780}}</ref><ref>{{cite patent| url= http://www.google.com/patents/US2835669 |country= US| status= patent |title= Process for the Production of Substituted Morpholines | number= 2835669 | gdate= 20 May 1958| fdate= 29 June 1953| inventor = Thomä O | assign1= C. H. Boehringer Sohn}}</ref> with some pharmacological data published in 1954.<ref name= thomae>{{cite journal| vauthors = Thomä O, Wick H | title=Über einige Tetrahydro-1,4-oxazine mit sympathicomimetischen Eigenschaften| journal=Arch. Exp. Pathol. Pharmakol.| volume=222| year=1954| issue=6| pages=540| doi=10.1007/BF00246905| s2cid=25143525}}</ref> It was the result of a search by Thomä and Wick for an [[anorectic]] drug without the side-effects of [[amphetamine]].<ref name=martel>{{cite journal | vauthors = Martel A | title = Preludin (phenmetrazine) in the treatment of obesity | journal = Canadian Medical Association Journal | volume = 76 | issue = 2 | pages = 117–120 | date = January 1957 | pmid = 13383418 | pmc = 1823494 }}</ref> Phenmetrazine was introduced into [[Clinical trial|clinical]] use in 1954 in [[Europe]].<ref name=kalant>{{cite book| vauthors = Kalant OJ | title=The Amphetamines: Toxicity and Addiction| year=1966| isbn=0-398-02511-8}}</ref>

== Medical use ==

In clinical use, phenmetrazine produces less [[Anxiety|nervousness]], hyperexcitability, [[Euphoria (emotion)|euphoria]] and [[insomnia]] than drugs of the amphetamine family.<ref name=jama>{{cite journal | vauthors = | title = Phenmetrazine hydrochloride | journal = Journal of the American Medical Association | volume = 163 | issue = 5 | pages = 357 | date = February 1957 | pmid = 13385162 }}</ref> It tends not to increase [[heart rate]] as much as other stimulants. Due to the relative lack of [[Adverse effect (medicine)|side effect]]s, one study found it well tolerated in children.<ref name=martel /> In a study of the effectiveness on [[weight loss]] between phenmetrazine and [[dextroamphetamine]], phenmetrazine was found to be slightly more effective.<ref name=hampson>{{cite journal | vauthors = Hampson J, Loraine JA, Strong JA | title = Phenmetrazine and dexamphetamine in the management of obesity | journal = Lancet | volume = 1 | issue = 7137 | pages = 1265–1267 | date = June 1960 | pmid = 14399386 | doi = 10.1016/S0140-6736(60)92250-9 }}</ref>

== Pharmacology ==

Phenmetrazine acts as a [[releasing agent]] of [[norepinephrine]] and [[dopamine]] with [[EC50|EC₅₀]] values of 50.4 ± 5.4 nM and 131 ± 11 nM, respectively.<ref name="pmid17017961">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1845–1859 | year = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 | url = http://www.bentham-direct.org/pages/content.php?CTMC/2006/00000006/00000017/0004R.SGM | access-date = 5 May 2020 | url-status = usurped | archive-url = https://web.archive.org/web/20170326103021/http://www.bentham-direct.org/pages/content.php?CTMC%2F2006%2F00000006%2F00000017%2F0004R.SGM | archive-date = 26 March 2017 }}</ref> It has negligible efficacy as a releaser of [[serotonin]], with an EC₅₀ value of only 7,765 ± 610 nM.<ref name="pmid17017961"/>

After an oral dose, about 70% of the drug is [[Excretion|excreted]] from the body within 24 hours. About 19% of that is excreted as the unmetabolised drug and the rest as various [[metabolite]]s.<ref name=clarkes>{{cite book| title=Clarke's Analysis of Drugs and Poisons| vauthors = Moffat AC, Osselton MD, Widdop D| year = 2004| isbn=0-85369-473-7}}</ref>

In trials performed on rats, it has been found that after [[Subcutaneous injection|subcutaneous]] administration of phenmetrazine, both [[optical isomer]]s are equally effective in reducing food intake, but in [[mouth|oral]] administration the [[Levorotation|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.<ref name=engelhardt>{{cite journal| title=Studies of the Mechanism of the Anti-Appetite Action of Phenmetrazine| vauthors = Engelhardt A | journal=Biochem. Pharmacol.| volume=8| issue=1| pages=100| year=1961| doi=10.1016/0006-2952(61)90520-2}}</ref>

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==

[[File:Phenmetrazine Synthesis.svg|center]]

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.<ref name="WO2011146850A1">{{cite patent | inventor = Blough BE, Rothman R, Landavazo A, Page KM, Decker AM | assign1 = Research Triangle Institute, | country = WO | number = 2011146850 | title = Phenylmorpholines and analogues thereof |url=https://patents.google.com/patent/WO2011146850A1/ }} pages 51,54–55</ref>

==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.<ref>{{cite web| url=http://www.druglibrary.org/schaffer/LIBRARY/studies/cu/CU39.html| title=The Swedish Experience| vauthors = Brecher EM | access-date=31 October 2009}}</ref> 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.<ref name="Milesp66-67">{{cite book| vauthors = Miles B | title= Paul McCartney: Many Years from Now| year= 1998| pages= [https://archive.org/details/paulmccartneyman00mile_0/page/66 66–67]| publisher= H. Holt| isbn= 0-8050-5248-8| url-access= registration| url= https://archive.org/details/paulmccartneyman00mile_0/page/66}}</ref> [[Hunter Davies]] asserted, in his 1968 biography of the band,<ref name="Davies78">{{cite book| author-link= Hunter Davies| vauthors = Davies H | title=The Beatles: The Authorized Biography| url= https://archive.org/details/beatlesauthorize00davi| url-access= registration| year=1968 |page=[https://archive.org/details/beatlesauthorize00davi/page/78 78]| publisher = New York, McGraw-Hill Book Co | isbn=0-07-015457-0}}</ref> 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]].<ref>{{cite book| vauthors = Ruby J |title= Testimony of Jack Ruby| volume= 5| publisher= US Government Printing Office| year= 1964| pages= 198–99}}</ref>

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".<ref>{{cite book |title=Rosa Lee |vauthors=Dash L |publisher=HarperCollins |year=1996 |page=108}}</ref> Phenmetrazine continues to be used and abused around the world, in countries including [[South Korea]].<ref>{{cite journal | vauthors = Choi H, Baeck S, Jang M, Lee S, Choi H, Chung H | title = Simultaneous analysis of psychotropic phenylalkylamines in oral fluid by GC-MS with automated SPE and its application to legal cases | journal = Forensic Science International | volume = 215 | issue = 1–3 | pages = 81–87 | date = February 2012 | pmid = 21377815 | doi = 10.1016/j.forsciint.2011.02.011 }}</ref>

== References ==

{{Reflist}}

{{Stimulants}}

{{Anorectics}}

{{Monoamine releasing agents}}

{{Phenethylamines}}

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{{Authority control}}

[[Category:Anorectics]]

[[Category:Beta-Hydroxyamphetamines]]

[[Category:Euphoriants]]

[[Category:Norepinephrine-dopamine releasing agents]]

[[Category:Phenylmorpholines]]

[[Category:Stimulants]]

[[Category:Withdrawn drugs]]