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| Routes of administration | Oral |
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| Eliminationhalf-life | 16 hours[2] |
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| Formula | C15H21N |
| Molar mass | 215.340 g·mol−1 |
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Fencamfamin (INN), also known asfencamfamine or by the brand namesGlucoenergan andReactivan, is astimulant which was developed by Merck in the 1960s.[3]
Fencamfamin is still used, though rarely, for treating depressive day-time fatigue, lack of concentration and lethargy, particularly in individuals who have chronic medical conditions, as its favourable safety profile makes it the most suitable drug in some cases.[4]
Fencamfamin is well tolerated and causes minimal circulatory effects. Extended use may result in a dryness of the mouth.[4]
Not to be used with heart diseases, angina pectoris and decompensated cardiac insufficiency, glaucoma, hyper-excitability and thyrotoxicosis or while treated with monoamine oxidase inhibitors.[4]
Symptoms of overdose are nausea, agitation and restlessness, dryness of the mouth, dizziness and tremor. In gross overdosage also associated with dyspnoea, tachycardia, disorientation and convulsions.[4]
In a study on slices of rat corpus striatum and substantia nigra fencamfamin acted as an indirectdopamine agonist. It releaseddopamine by a similar mechanism to amphetamines, but was ten times less potent than dexamphetamine at producing this effect. The main mechanism of action was instead inhibition of dopaminereuptake. Also unlikeamphetamines, fencamfamin does not inhibit the action ofmonoamine oxidase enzymes. It was concluded that, at least in the models employed, the in vitro profile of fencamfamin is more similar to that ofnomifensine, a reportedly pure uptake inhibitor, than to d-amphetamine.[5]
In animal experiments onplace preference fencamfamin produced a significant place preference only at the dose of 3.5 mg/kg. The experiments suggested a relation to dopamine D1 receptors, and also toopioid receptors in the reinforcement produced by fencamfamin, as place preference was blocked by the selective dopamine D1 antagonistSCH 23390 and by the opioid antagonistnaloxone.[6] A similar place preference, which was blocked bynaloxone and bySCH 23390 and byraclopride, has been seen in a study on rats with drinking water. Animals treated with naloxone before the conditioning sessions showed a place aversion instead of the place preference found in saline-treated animals. Naloxone also reduced drinking. It was proposed that naloxone induced a state of frustrative nonreward. It was suggested that both dopamine and (endogenous) opioids are important for water-induced reinforcement. Possible interactions between these two neurotransmitter systems were discussed.[7]
Fencamfamin may be synthesized in a straightforward fashion via theDiels-Alder reaction betweencyclopentadiene andβ-nitrostyrene (1-nitro-2-phenyl-ethene). The C=C double bond and thenitro-group in the resultingnorcamphene derivative are then reduced to give the saturatednorcamphane derivative. Finally, theamino-group is ethylated.
Although β-nitrostyrene is commercially available, it is also very easily prepared using theHenry Reaction betweenbenzaldehyde andnitromethane.[8]
The Diels-Alder reaction ofβ-nitrostyrene and cyclopentadiene is described in a number of early papers.[9][10]
The reduction of thenitroalkene may be carried out sequentially. Thealkene's double bond is typically reduced using hydrogen and atransition metalcatalyst like Ni or Pt, while the nitro group is reduced to the amine with a metal/acid combination, such as Fe/HCl.[10] The reduction of both functional groups can also be achieved simultaneously by the use ofRaney nickel,[10] and this transformation has recently been optimized by Russian chemists.[11]
Originally achieved underreductive amination conditions involving the reaction of the amine withacetaldehyde in the presence of Pt, ethylation of the amino-group has been improved by the use of Ra-Ni and ethanol.[11]
Thestereochemical consequences of the steps involved in the reaction sequence outlined above have been studied. Thus, the Diels-Aldercycloaddition leads to a product in which the nitro- and phenyl- groups are in a trans- relationship to each other.[12] This product is actually a mixture ofstereoisomers, in which the pair ofenantiomers having the nitro- group in the endo- position and the phenyl- group in the exo- position predominates over the enantiomeric pair with exo-nitro and endo-phenyl groups. Although the isomeric composition of the Diels-Alderadduct itself does not seem to have been determined, Poos et al. reported a ratio of ~3:1 for thesaturated un-ethylated amine derived from it.[13] Novakov and co-workers, citing a thesis study,[14] report that the corresponding ratio of endo-N-ethyl/exo-Φ : exo-N-ethyl/endo-Φ enantiomeric pairs is ~9:1 in fencamfamin itself.[11]
