 | |
| Clinical data | |
|---|---|
| Trade names | Preludin, others |
| Other names | Fenmetrazine; 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 |
|
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Eliminationhalf-life | 8 hours[citation needed] |
| Excretion | Kidney[citation needed] |
| Identifiers | |
| |
| CAS Number |
|
| PubChemCID | |
| DrugBank |
|
| ChemSpider |
|
| UNII | |
| KEGG |
|
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.004.677 |
| Chemical and physical data | |
| Formula | C11H15NO |
| Molar mass | 177.247 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
| (verify) | |
Phenmetrazine, sold under the brand namePreludin among others, is astimulantdrug firstsynthesized in 1952 and originally used as anappetite suppressant, butwithdrawn from the market in the 1980s due to widespreadmisuse. It was initially replaced by itsanaloguephendimetrazine (under the brand name Prelu-2) which functions as aprodrug to phenmetrazine, but now it is rarely prescribed, due to concerns of misuse andaddiction. Chemically, phenmetrazine is asubstituted amphetamine containing amorpholinering or asubstituted phenylmorpholine.
Phenmetrazine has been used as anappetite suppressant for purposes ofweight 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 todextroamphetamine in people withobesity.[3]
In addition to its appetite suppressant effects, phenmetrazine producespsychostimulant andsympathomimetic effects.[4][5][2] Phenmetrazine has been shown to produce very similar subjective psychostimulant effects to those ofamphetamine andmethamphetamine in clinical studies.[4][5] Although able to produce comparable effects however, phenmetrazine has only about one-fifth to one-third of thepotency ofdextroamphetamine by weight.[5][4][3]
Phenmetrazine acts as anorepinephrine and dopamine releasing agent (NDRA), withEC50Tooltip half-maximal effective concentration values for induction ofnorepinephrine anddopamine release of 29–50 nM and 70–131 nM, respectively.[6][7][8][9][10] It has very weak activity as a releaser ofserotonin, with an EC50 value of 7,765 to >10,000 nM.[6][7][8][9][10] The drug is several times lesspotent thandextroamphetamine anddextromethamphetamine as an NDRAin vitro.[6][7][8][9][10] This is in accordance with the higher doses required clinically.[5][4][3]
| 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] |
| (+)-Phenmetrazine | 37.5 | 87.4 | 3246 | [7] |
| (–)-Phenmetrazine | 62.9 | 415 | >10,000 | [7] |
| Phendimetrazine | >10,000 | >10,000 | >100,000 | [7][8][15] |
| Pseudophenmetrazine | 514 | >10,000 (RI) | >10,000 | [7] |
| (+)-Pseudophenmetrazine | 349 | 1,457 | >10,000 | [7] |
| (–)-Pseudophenmetrazine | 2,511 | IA (RI) | >10,000 | [7] |
| Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. Theassays were done in rat brainsynaptosomes and humanpotencies may be different. See alsoMonoamine releasing agent § Activity profiles for a larger table with more compounds.Refs:[17][6] | ||||
In contrast to many othermonoamine releasing agents (MRAs), phenmetrazine is inactive in terms ofvesicular monoamine transporter 2 (VMAT2) actions.[11][18] A few other MRAs have also been found to be inactive at VMAT2, such asphentermine andbenzylpiperazine (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 thetrace amine-associated receptor 1 (TAAR1).[19][20]
Phenmetrazine has been found todose-dependently elevate brain dopamine levels in rodentsin vivo.[7] A 10 mg/kgi.v. dose of phenmetrazine increasednucleus accumbens dopamine levels by around 1,400% in rats.[7] For comparison,dextroamphetamine 3 mg/kgi.p. increasedstriatal 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 proposeddopamine transporter (DAT) "inverse agonists"methylphenidate andcocaine (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 aftersubcutaneous administration of phenmetrazine, bothoptical isomers are equally effective in reducing food intake, but inoral administration thelevo 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]
After an oral dose, about 70% of the drug isexcreted from the body within 24 hours. About 19% of that is excreted as the unmetabolised drug and the rest as variousmetabolites.[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 similarbioavailability as well as time to peak onset, however, sustained-release formulations offer improvedpharmacokinetics with a steady release ofactive ingredient which results in a lower peak concentration in blood plasma.
Phenmetrazine, also known as (2RS,3RS)-2-phenyl-3-methylmorpholine or as (2RS,3RS)-3-methyl-2-phenyltetrahydro-2H-1,4-oxazine, is asubstituted phenylmorpholine.[25] It is the (2RS,3RS)- or (±)-trans-enantiomer of 2-phenyl-3-methylmorpholine.[25]
Phenmetrazine'schemical structure incorporates the backbone ofamphetamine, the prototypical psychostimulant which, like phenmetrazine, is areleasing agent of dopamine and norepinephrine. The molecule also loosely resemblesethcathinone, the active metabolite of popular anorecticamfepramone (diethylpropion). Unlike phenmetrazine, ethcathinone (and therefore amfepramone as well) are mostly selective asnorepinephrine releasing agents.
A variety of phenmetrazineanalogues andderivatives have been encountered asdesigner drugs.[26] In addition, the activities of various phenmetrazine analogues and derivatives asmonoamine releasing agent (MRA) have been described.[7][26][10]
Phenmetrazine can be synthesized in three steps from 2-bromopropiophenone andethanolamine. The intermediate alcohol 3-methyl-2-phenylmorpholin-2-ol (1) is converted to a fumarate salt (2) withfumaric acid, then reduced withsodium 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 was firstpatented inGermany in 1952 byBoehringer-Ingelheim,[27][28] with somepharmacological data published in 1954.[29] It was the result of a search by Thomä and Wick for ananorectic drug without theside effects ofamphetamine.[30] Phenmetrazine was introduced into clinical use in 1954 inEurope.[31]
Phenmetrazine is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name, andBANTooltip British Approved Name.[25][32][33] It is also known by the brand name Preludin.[25]
In 2004, phenmetrazine remained marketed only inIsrael.[33][32]
Phenmetrazine is aSchedule IIcontrolled substance in theUnited States.[34]
Phenmetrazine has been used recreationally in many countries, includingSweden. When stimulant use first became prevalent in Sweden in the 1950s, phenmetrazine was preferred toamphetamine andmethamphetamine by users.[35] In the autobiographical novelRush byKim Wozencraft, intravenous phenmetrazine is described as the most euphoric and pro-sexual of the stimulants the author used.
Phenmetrazine was classified as anarcotic in Sweden in 1959, and was taken completely off the market in 1965. Formerly the illegal demand was satisfied by smuggling fromGermany, and laterSpain andItaly. 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 bythe Beatles early in their career.Paul McCartney was one known user. McCartney's introduction to drugs started inHamburg,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 byAstrid Kirchherr (whose mother bought them). McCartney would usually take one, butJohn 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 killedLee 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 includingSouth Korea.[40]
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.
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).
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.
[...] Table 3. Monoamine Release and 5HT2B Activity of a 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
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.
RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays.
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.
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.
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.
