Tranylcypromine

Tranylcypromine

Systematic (IUPAC) name
(±)-trans-2-phenylcyclopropan-1-amine or (1R*,2S*)-2-phenylcyclopropan-1-amine
Clinical data
Trade names	Parnate
AHFS/Drugs.com	monograph
MedlinePlus	a682088
Pregnancy cat.	C
Legal status	℞ Prescription only
Routes	Oral
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]
Identifiers
CAS number	155-09-9 Y
ATC code	N06AF04
PubChem	CID 19493
DrugBank	DB00752
ChemSpider	18369 Y
UNII	3E3V44J4Z9 N
ChEMBL	CHEMBL1179 N
Synonyms	Transamine
Chemical data
Formula	C9H11N
Mol. mass	133.19 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C9H11N/c10-9-6-8(9)7-4-2-1-3-5-7/h1-5,8-9H,6,10H2/t8-,9+/m0/s1 Y Key:AELCINSCMGFISI-DTWKUNHWSA-N Y
N(what is this?)  (verify)

Tranylcypromine (Parnate, Jatrosom) is a drug of the substituted phenethylamine and amphetamine classes which acts as a monoamine oxidase inhibitor (MAOI)—it is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase (MAO).^[1][2] It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.

History

Tranylcypromine was originally developed as an analogue of amphetamine.^[1] Although it was first synthesized in 1948,^[3] its MAOI action was not discovered until 1959. Precisely because tranylcypromine 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.^[4]

The drug was introduced by Smith, Kline & French in the United Kingdom in 1960 and approval in the United States soon followed in 1961.^[5] It was withdrawn from the market in February 1964 due to a number of patient deaths involving hypertensive crises with intracranial bleeding. However, it was reintroduced later that year with more limited indications and specific warnings of the risks.^[6]

Clinical use

Despite their well-established efficacy, indications for monoamine oxidase inhibitors are currently very limited, due to their significant potential for adverse effects, many interactions, and the availability of newer and safer (although not necessarily more efficacious) antidepressants.^[2] Tranylcypromine is indicated primarily for the treatment of major depressive disorder, and can also be used in the management of various mood and anxiety disorders, typically as a last resort after conventional antidepressants have been tried without success.

Effectiveness

Tranylcypromine is highly effective in the treatment of anergic depression in comparison to placebo.^[7] In comparison to imipramine, tranylcypromine has been shown to be more effective in anergic bipolar depression, and results in fewer patients leaving treatment.^[8] As contrasted with alprazolam, carbamazepine, and trifluoperazine, only tranylcypromine was effective in increasing the favorability of patients' self-evaluations in the treatment of women with borderline personality disorder.^[9] Tranylcypromine has shown substantial effectiveness in treatment-resistant depression, with,^[10][11] or, at unusually high dosages, without,^[12] lithium. However, at normal dosages, tranylcypromine proved no more effective than venlafaxine and mirtazapine in treatment-resistant depression, and was associated with worse side effects.^[13]

Contraindications

Main article: Monoamine oxidase inhibitor

Therapeutic contraindications of tranylcypromine include:

• Cardiovascular or cerebrovascular disease
• Drug abuse (due to the potential for interactions with certain agents, especially stimulants)
• Low body weight, anorexia, or eating disorders of the sort
• Pheochromocytoma
• Pre-existing and chronic headaches or migraines
• Psychosis such as schizophrenia or bipolar disorder

Dietary restrictions

Main article: Foods containing tyramine

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, 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).

At least one case of the abuse of tranylcypromine has been noted. Sequelae included the periodic elimination of REM sleep and substantially elevated nocturnal muscle tone. Attempts to discontinue the medication resulted in nightmares accompanied by prompt and grossly excessive nocturnal REM sleep, and narcolepsy.^[14]

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.

Pharmacology

Tranylcypromine 10 mg tablets.

Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase.^[1][2] Regarding the isoforms of monoamine oxidase, it shows slight preference for the MAO_B isoenzyme over MAO_A. In addition, tranylcypromine functions as a norepinephrine and dopamine releasing agent (NDRA) with approximately 1/10 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.^[15]

Chemistry

Synthesis

Several methods of chemical synthesis for tranylcypromine are known.

Traditional:^[3]

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 stereoisomers 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.

Modern:^[16]

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.

See also

• Monoamine oxidase inhibitor
• Phenelzine
• Amphetamine

References

1. ^ ^{a b c d e f} Williams, David A. (2007). = R0W1ErpsQpkC&pg = PA590 "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 c} Baldessarini, Ross J. (2005). "17. Drug therapy of depression and anxiety disorders". In Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics. New York: McGraw-Hill. ISBN 0071422803. 
3. ^ ^{a b} Burger, A.; Yost, W. L. (1948). Journal of the American Chemical Society 70 (6): 2198. doi:10.1021/ja01186a062.  edit
4. ^ 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
5. ^ Shorter, Edward (2009). Before Prozac: the troubled history of mood disorders in psychiatry. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-536874-6. http://books.google.com/?id=8VaYF8pIPxgC&lpg=PR13&pg=PR13#v=onepage&q. 
6. ^ Council on Drugs. Reevaluation of tranylcypromine sulfate. JAMA 189(10): 763-764, 1964.
7. ^ A Double-Blind Study of Tranylcypromine Treatment of Major Anergic Depression
8. ^ Tranylcypromine versus imipramine in anergic bipolar depression Am J Psychiatry 1991;148:910-916.
9. ^ Pharmacotherapy of Borderline Personality Disorder Arch Gen Psychiatry. 1988;45(2):111-119.
10. ^ Efficacy of lithium-tranylcypromine treatment in refractory depression Am J Psychiatry 1985;142:619-623.
11. ^ Treatment of Previously Intractable Depressions With Tranylcypromine and Lithium
12. ^ High dose tranylcypromine therapy for refractory depression Pharmacopsychiatry. 1989 Jan;22(1):21-5.
13. ^ Tranylcypromine Versus Venlafaxine Plus Mirtazapine Following Three Failed Antidepressant Medication Trials for Depression: A STAR*D Report Am J Psychiatry 2006;163:1531-1541.
14. ^ The Clinical State, Sleep and Amine Metabolism of a Tranylcypromine (`Parnate') Addict The British Journal of Psychiatry (1965) 111: 357-364
15. ^ 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
16. ^ Rajadhyaksha, V.J. (1977). "Method of synthesis of trans-2-phenylcyclopropylamine" U.S. Patent 4,016,204