Phenmetrazine

Effects

Overview

Stimulant drug that was previously used as an appetite suppresant, has been withdrawn from the market, due to concerns of abuse and addiction. Usually produces less nervousness, euphoria, and insomnia than drugs of the amphetamine family. Also as a study concluded, it is slightly more effective than dextroamphetamine as a weight loss agent. TS

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among others, is a stimulant drug first synthesized in 1952 and originally used as an appetite suppressant, but withdrawn from the market in the 1980s due to widespread misuse.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. WP

History

History

Phenmetrazine was first patented in Germany in 1952 by Boehringer-Ingelheim, with some pharmacological data published in 1954. It was the result of a search by Thomä and Wick for an anorectic drug without the side effects of amphetamine. Phenmetrazine was introduced into clinical use in 1954 in Europe.[1–5] WP

Legal status

Names

Phenmetrazine is the generic name of the drug and its INN (International Nonproprietary Name), USAN (United States Adopted Name), and BAN (British Approved Name). It is also known by the brand name Preludin.[6][7][8] WP

Availability

In 2004, phenmetrazine remained marketed only in Israel.[7][8] WP

Legal status

Phenmetrazine is a Schedule II controlled substance in the United States.[9] WP

Pharmacology

Pharmacodynamics

Phenmetrazine acts as a norepinephrine–dopamine releasing agent (NDRA), with EC₅₀ (half-maximal effective concentration) values for induction of norepinephrine and dopamine release of 29–50 nM and 70–131 nM, respectively. It has very weak activity as a releaser of serotonin, with an EC₅₀ value of 7,765 to >10,000 nM. The drug is several times less potent than dextroamphetamine and dextromethamphetamine as an NDRA in vitro. This is in accordance with the higher doses required clinically.[10–17] WP⚠ A table follows this text in the source and is not copied here. Open the source to see it.

In contrast to many other monoamine releasing agents (MRAs), phenmetrazine is inactive in terms of vesicular monoamine transporter 2 (VMAT2) actions. A few other MRAs have also been found to be inactive at VMAT2, such as phentermine and benzylpiperazine (BZP). These findings indicate that VMAT2 activity is non-essential for robust MRA actions.[18][19] WP

Phenmetrazine does not appear to have been assessed at the trace amine-associated receptor 1 (TAAR1).[20][21] WP

Phenmetrazine has been found to dose-dependently elevate brain dopamine levels in rodents in vivo. A 10 mg/kg i.v. dose of phenmetrazine increased nucleus accumbens dopamine levels by around 1,400% in rats. For comparison, dextroamphetamine 3 mg/kg i.p. increased striatal dopamine levels by about 5,000% in rats. 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%). 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. However, the pharmacological significance of these VMAT2 interactions in humans is unclear.[11][22][23] WP

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.[24] WP

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.[25] WP

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. WP

Chemistry

Formula

C11H15NO PC

CAS number

134-49-6 PC

Molar mass (g/mol)

177.24 PC

IUPAC name (computed by PubChem)

3-methyl-2-phenylmorpholine PC

SMILES

CC1C(OCCN1)C2=CC=CC=C2 PC

InChIKey

OOBHFESNSZDWIU-UHFFFAOYSA-N PC

PubChem CID

4762

IUPAC name

3-methyl-2-phenylmorpholine WP

Pop culture

No references added yet.

References

1. Other Improvements in or relating to the preparation of substituted morpholines
2. Other Process for the Production of Substituted Morpholines
3. Journal / agency Thomä O, Wick H. Über einige Tetrahydro-1,4-oxazine mit sympathicomimetischen Eigenschaften. Arch. Exp. Pathol. Pharmakol. 1954. doi:10.1007/BF00246905
4. Journal / agency Martel A. Preludin (phenmetrazine) in the treatment of obesity. Canadian Medical Association Journal. January 1957. PMID 13383418 · PMC1823494
5. Other Kalant OJ. The Amphetamines: Toxicity and Addiction. 1966
6. Other Elks J. The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. 2014
7. Other Schweizerischer Apotheker-Verein. Index Nominum 2000: International Drug Directory. 2000
8. Other Schweizerischer Apotheker-Verein. Index Nominum: International Drug Directory. 2004
9. Journal / agency Bray GA, Purnell JQ. An Historical Review of Steps and Missteps in the Discovery of Anti-Obesity Drugs. 10 July 2022. PMID 35834619
10. Journal / agency Rothman RB, Baumann MH. Therapeutic potential of monoamine transporter substrates. Current Topics in Medicinal Chemistry. 2006. doi:10.2174/156802606778249766 · PMID 17017961
11. Journal / agency Rothman RB, Katsnelson M, Vu N, Partilla JS, Dersch CM, Blough BE, Baumann MH. Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain. European Journal of Pharmacology. June 2002. doi:10.1016/s0014-2999(02)01830-7 · PMID 12106802
12. Other Blough B. Dopamine Transporters: Chemistry, Biology and Pharmacology. July 2008
13. Journal / agency McLaughlin G, Baumann MH, Kavanagh PV, Morris N, Power JD, Dowling G, Twamley B, O'Brien J, Hessman G, Westphal F, Walther D, Brandt SD. Synthesis, analytical characterization, and monoamine transporter activity of the new psychoactive substance 4-methylphenmetrazine (4-MPM), with differentiation from its ortho- and meta- positional isomers. Drug Test Anal. September 2018. doi:10.1002/dta.2396 · PMID 29673128 · PMC7316143
14. Other Phenylmorpholines and analogues thereof. 20 May 2011
15. Journal / agency Martin WR, Sloan JW, Sapira JD, Jasinski DR. Physiologic, subjective, and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man. Clin Pharmacol Ther. 1971. doi:10.1002/cpt1971122part1245 · PMID 5554941
16. Journal / agency Chait LD, Uhlenhuth EH, Johanson CE. The discriminative stimulus and subjective effects of d-amphetamine, phenmetrazine and fenfluramine in humans. Psychopharmacology (Berl). 1986. doi:10.1007/BF00174364 · PMID 3088654
17. Journal / agency Hampson J, Loraine JA, Strong JA. Phenmetrazine and dexamphetamine in the management of obesity. Lancet. June 1960. doi:10.1016/S0140-6736(60)92250-9 · PMID 14399386
18. Journal / agency Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL. Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter. Drug Alcohol Depend. February 2015. doi:10.1016/j.drugalcdep.2014.12.005 · PMID 25548026 · PMC4297708
19. Journal / agency Partilla JS, Dempsey AG, Nagpal AS, Blough BE, Baumann MH, Rothman RB. Interaction of amphetamines and related compounds at the vesicular monoamine transporter. J Pharmacol Exp Ther. October 2006. doi:10.1124/jpet.106.103622 · PMID 16835371
20. Other PDSP Database
21. Other Liu T. Binding Database Home. 31 December 2024
22. Journal / agency Heal DJ, Gosden J, Smith SL. Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine. Neuropharmacology. December 2014. doi:10.1016/j.neuropharm.2014.06.012 · PMID 24953830
23. Journal / agency Reith ME, Gnegy ME. Molecular Mechanisms of Amphetamines. Handb Exp Pharmacol. 2020. doi:10.1007/164_2019_251 · PMID 31286212
24. Journal / agency Engelhardt A. Studies of the Mechanism of the Anti-Appetite Action of Phenmetrazine. Biochem. Pharmacol. 1961. doi:10.1016/0006-2952(61)90520-2
25. Other Moffat AC, Osselton MD, Widdop D. Clarke's Analysis of Drugs and Poisons. 2004

Text and values on this page are quoted from Wikipedia (CC BY-SA 4.0), TripSit factsheets, PubChem (public domain). Each value links to the exact revision it came from.