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among others, is a stimulant drug first synthesized in 1952 and originally used as an appetite suppressant, but withdrawn from the market in the 1980s due to widespread misuse.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 Phenmetrazine has been used as an appetite suppressant for purposes of weight loss. 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. Phenmetrazine has been found to produce similar weight loss to dextroamphetamine in people with obesity. In addition to its appetite suppressant effects, phenmetrazine has been shown to produce very similar subjective psychostimulant effects to those of amphetamine and methamphetamine in clinical studies, although only about one-fifth to one-third of the potency of dextroamphetamine by weight.
Pharmacology
Pharmacodynamics Phenmetrazine acts as a norepinephrine–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. 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.
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. Phenmetrazine does not appear to have been assessed at the trace amine-associated receptor 1 (TAAR1). 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. 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.
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. 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. It is the (2RS,3RS)- or (±)-trans- enantiomer of 2-phenyl-3-methylmorpholine. 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. In addition, the activities of various phenmetrazine analogues and derivatives as monoamine releasing agent (MRA) have been described.
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.
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.
Society and culture
Names Phenmetrazine is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, and BANTooltip British Approved Name. It is also known by the brand name Preludin.
Availability In 2004, phenmetrazine remained marketed only in Israel.
Legal status Phenmetrazine is a Schedule II controlled substance in the United States.
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