Tranylcypromine: Wikis

  

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1 : 1 mixture (racemate)
Systematic (IUPAC) name
(±)-trans-2-phenylcyclopropyl-1-amine
Identifiers
CAS number 155-09-9
ATC code N06AF04
PubChem 19493
DrugBank DB00752
Chemical data
Formula C 9H11N 
Mol. mass 133.19 g/mol
SMILES eMolecules & PubChem
Synonyms Transamine
Pharmacokinetic data
Bioavailability 50%[1]
Metabolism Liver (by enzymes CYP2A6, CYP2C19, CYP2D6, MAOA, and MAOB)
Half life 2.5 hours[1]
Excretion Urine, feces[1]
Therapeutic considerations
Pregnancy cat. C
Legal status Uncontrolled
Routes Oral
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Tranylcypromine (Parnate, Jatrosom) is a psychoactive drug of the phenethylamine and amphetamine chemical classes which acts as a monoamine oxidase inhibitor (MAOI)—it is a nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO).[1] It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.

Contents

Clinical use

Tranylcypromine is indicated primarily for the treatment of major depression without melancholia. It is generally used to remedy various types of mood and anxiety disorders, typically after a last resort only after conventional antidepressants have been tried without success. It also has some off-label uses, such as in the treatment of post-traumatic stress disorder (PTSD).

Contraindications

Therapeutic contraindications of tranylcypromine include:

Dietary restrictions

Foods high in endogenous monoamine precursors or exogenous monoamine compounds may cause adverse reactions. The most common example of this, is the hypertensive crisis caused by the ingestion of tyramine, which is found in foods like aged cheeses, cured meats, tofu and certain red wines. Some, such as yeast extracts like Bovril and Marmite, contain enough tyramine to be potentially fatal in a single serving. Spoiled food is also likely to contain dangerous levels of tyramine.

Adverse effects

Adverse effects of tranylcypromine may include anxiety or nervousness, irritability, anorexia and subsequent weight loss, insomnia, mydriasis, tachycardia, hypertension or hypotension, hyperthermia, increased perspiration, muscle tremors, sexual dysfunction consisting of erectile dysfunction and/or anorgasmia, and orthostatic or postural hypotension.

Tranylcypromine is typically considered to have fewer side effects than the hydrazines, such as phenelzine (Nardil).

Overdose

Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects. They may include exacerbated anxiety, muscle tremors, tachycardia, hypertension or hypotension, and hyperthermia, among others. Rare cases have been reported of hypertensive crisis, serotonin syndrome, myoclonus, hyperpyrexia, psychosis, and delirium, some of which progressed to coma. Additionally, in sensitive individuals or at extreme dosages, hypotension may lead to shock.

Chemistry

Tranylcypromine was developed as the cyclopropyl analogue of amphetamine.[1] Although it was first synthesized in 1948,[2] its MAOI action was not discovered until 1959, in Smith, Kline & French Laboratories. Precisely because tranyl was not, like isoniazid and iproniazid, a hydrazine derivative, its clinical interest increased enormously, as it was thought that it might have a more acceptable therapeutic index than previous MAOIs.[3]

Several methods of chemical synthesis for tranylcypromine are known. Traditional:[2]

  1. Styrene is reacted with ethyl diazoacetate to give ethyl 2-phenylcyclopropanecarboxylate.
  2. Hydrolysis of ethyl 2-phenylcyclopropanecarboxylate in the presence of alkali forms 2-phenylcyclopropanecarboxylic acid.
  3. 2-phenylcyclopropanecarboxylic acid is reacted with thionyl chloride (SOCl2) to form 2-phenylcyclopropanecarbonyl chloride.
  4. 2-phenylcyclopropanecarbonyl chloride is reacted with sodium azide (NaN3).
  5. The resulting azide of the above step is then the subject of a Curtius rearrangement.
  6. The resulting isocyanate of the above step is hydrolyzed in a Schmidt reaction to realize 2-phenylcyclopropylamine as the product.
  7. There are now four steroisomers of the final compound:
    • (1S,2R)-trans-2-phenylcyclopropylamine
    • (1R,2S)-trans-2-phenylcyclopropylamine
    • (1R,2R)-cis-2-phenylcyclopropylamine
    • (1S,2S)-cis-2-phenylcyclopropylamine
  8. The required racemate of (1S,2R)- and (1R,2S)-trans-2-phenylcyclopropylamine is separated from (1R,2R)- and (1S,2S)-cis-2-phenylcyclopropylamine by crystalization with enantiopure tartaric acid, resulting in tranylcypromine.

TranylcypromineScheme.svg

Modern:[4]

  1. Styrene is reacted with ethyl diazoacetate to give ethyl 2-phenylcyclopropanecarboxylate.
  2. Product is 3-4 parts trans isomer and 1-2 parts of cis isomer.
  3. Ethyl 2-phenylcyclopropanecarboxylate is epimerized by refluxing in sodium/ethanol. At the end of the reflux, ratio = 95% trans and 5% cis.
  4. Further purification through recrystallization at this stage results in pure racemic trans product.
  5. Hydrolysis of ethyl 2-phenylcyclopropanecarboxylate in the presence of alkali forms 2-phenylcyclopropanecarboxylic acid.
  6. 2-phenylcyclopropanecarboxylic acid is reacted with thionyl chloride (SOCl2) to form 2-phenylcyclopropanecarbonyl chloride.
  7. 2-phenylcyclopropanecarbonyl chloride is reacted with sodium azide (NaN3).
  8. The resulting azide of the above step is then the subject of a Curtius rearrangement.
  9. The resulting isocyanate of the above step is hydrolyzed to 2-phenylcyclopropylamine.
  10. The racemate can be purified further into the (–)-enantiomer via crystalization with the (+)-enantiomer of tartaric acid.

(1R,2S)-trans-2-phenylcyclopropylamine

Tranylcypromine synthesis.png

Pharmacology

Tranylcypromine 10 mg tablets.

As mentioned above, tranylcypromine acts as a nonselective and irreversible monoamine oxidase inhibitor. Regarding the isoforms of monoamine oxidase, it shows slight preference for the MAOB isoenzyme over MAO-A. In addition, tranylcypromine functions as a norepinephrine and dopamine releasing agent (NDRA) with approximately 1/10th the potency of amphetamine.

As a result of these actions, tranylcypromine considerably boosts the concentrations and activity of the monoamine neurotransmitters serotonin and dopamine, along with paradoxical and varying effects on norepinephrine and epinephrine. It increases the levels of the trace amines phenethylamine, tyramine, octopamine, and tryptamine as well. It is believed to be tranylcypromine's action on these neurochemicals that is responsible for its therapeutic efficacy.

Tranylcypromine has also been shown to inhibit the histone demethylase, BHC110/LSD1. Tranylcypromine inhibits this enzyme with an IC50 < 2 µM, thus acting as a small molecule inhibitor of histone demethylation with an effect to derepress the transcriptional activity of BHC110/LSD1 target genes[5].

See also

  • Cyclopentamine (which is N-methyl-2-cyclopentylpropylamine)
  • Cypenamine (which is trans-2-phenylcyclopentylamine)
  • DMCPA (which is 4-methyl-2,5-dimethoxycyclopropylamine)
  • Propylhexedrine (which is N-methyl-2-cyclohexylpropylamine)

References

  1. ^ a b c d e Williams, David A. (2007). "Antidepressants". in Foye, William O.; Lemke, Thomas L.; Williams, David A.. Foye's Principles of Medicinal Chemistry. Hagerstwon, MD: Lippincott Williams & Wilkins. pp. 590–1. ISBN 0-7817-6879-9. http://books.google.com/books?id=R0W1ErpsQpkC&pg=PA590.  
  2. ^ a b Burger, A.; Yost (1948). Journal of the American Chemical Society 70: 2198. doi:10.1021/ja01186a062.   edit
  3. ^ López-Muñoz, F; Alamo (2009). "Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today". Current pharmaceutical design 15 (14): 1563–86. doi:10.2174/138161209788168001. PMID 19442174.   edit
  4. ^ Rajadhyaksha, V.J. (1977). "Method of synthesis of trans-2-phenylcyclopropylamine" U.S. Patent 4,016,204
  5. ^ Lee; Wynder, C.; Schmidt, D.; McCafferty, D.; Shiekhattar, R. (2006). "Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications". Chemistry & biology 13 (6): 563–567. doi:10.1016/j.chembiol.2006.05.004. PMID 16793513.   edit







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