(1 R*,2 S*)-2-phenylcyclopropan-1-amine
Trade names Parnate
Pregnancy cat. B2
( C AU) ( US)
Prescription Only (S4) ( AU) ℞ -only ( CA) POM ( UK) ℞ -only ( US) ℞ P rescription only
Liver (by enzymes CYP2A6, CYP2C19, CYP2D6, MAO, and A MAO) B
Half-life 2.5 hours
Urine, Feces [1 ]
C 9 H 11 N
Mol. mass 133.19 g/mol
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Tranylcypromine (brand names: Parnate, Jatrosom (which is a brand solely sold in Germany)) is a drug of the substituted phenethylamine and amphetamine 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 [2 ] antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.
History [ edit ]
Tranylcypromine was originally developed as an
analog of amphetamine. Although it was first synthesized in 1948, [1 ] its MAOI action was not discovered until 1959. Precisely because tranylcypromine was not, like [3 ] isoniazid and iproniazid, a hydrazine derivative, its clinical interest increased enormously, as it was thought it might have a more acceptable therapeutic index than previous MAOIs. [4 ]
The drug was introduced by
Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961. It was withdrawn from the market in February 1964 due to a number of patient deaths involving hypertensive crises with intracranial bleeding.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. [5 ] [6 ]
Clinical use [ edit ]
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. Tranylcypromine is indicated primarily for the treatment of [2 ] 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 [ edit ]
Tranylcypromine is highly effective in the treatment of
anergic depression in comparison to placebo. In comparison to [7 ] imipramine, tranylcypromine has been shown to be more effective in anergic bipolar depression, and results in fewer patients leaving treatment. As contrasted with [8 ] 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. Tranylcypromine has shown substantial effectiveness in [9 ] treatment-resistant depression, with, [10 ] or, at unusually high dosages, without, [11 ] [12 ] lithium. However, at normal dosages, tranylcypromine proved no more effective than combination venlafaxine and mirtazapine in treatment-resistant depression, and was associated with more intolerance of side effects. [13 ]
Contraindications [ edit ]
contraindications of tranylcypromine include:
Dietary restrictions [ edit ]
Foods high in
endogenous monoamine precursors or exogenous monoamine compounds may cause adverse reactions. The most common example, hypertensive crisis, is caused by the ingestion of tyramine, which is found in foods such as 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 [ edit ]
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 [ edit ]
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 [ edit ]
Tranylcypromine 10-mg tablets
Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase.
[1 ] Regarding the [2 ] isoforms of monoamine oxidase, it shows slight preference for the MAOB isoenzyme over MAOA. In addition, tranylcypromine functions as a norepinephrine and dopamine releasing agent 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. Tranylcypromine's action on these neurochemicals are believed to be 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 ]
Synthesis [ edit ]
original [ edit ]
Several methods of
chemical synthesis for tranylcypromine are known.
Ralph E Tedeschi; Smith, Kline & French Lab (1961). U.S. Patent 2,997,422
Revised [ edit ]
Styrene is reacted with ethyl diazoacetate to give ethyl 2-phenylcyclopropanecarboxylate. Product is 65%
trans isomer and 35% cis isomer. Ethyl 2-phenylcyclopropanecarboxylate is
epimerized by refluxing in sodium/ethanol. At the end of the reflux, ratio = 95% trans and 5% cis. Hydrolysis is achieved by refluxing in a solution of NaOH with aqueous ethanol solvent for 20hr. After crystallizing with HCl, pure
trans carboxylic acid obtained. 2-Phenylcyclopropanecarboxylic acid is reacted with
thionyl chloride (SOCl 2) to form 2-phenylcyclopropanecarbonyl chloride. 2-Phenylcyclopropanecarbonyl chloride is reacted with
sodium azide (NaN 3). The resulting
azide of the above step is then the subject of a Curtius rearrangement. The resulting
isocyanate of the above step is hydrolyzed to 2-phenylcyclopropylamine. The racemate can be purified further into the (–)-enantiomer via crystallization with the (+)-enantiomer of
Rajadhyaksha, V.J. (1977). "Method of synthesis of trans-2-phenylcyclopropylamine"
U.S. Patent 4,016,204
N.B. In Schmidt reaction where -CO 2H reacted with HN directly. Alternatively,( 3 DPPA can convert carboxylic acid to azide in one-step Bromadol page)
See also [ edit ]
References [ edit ]
This article needs additional citations for . verification (August 2009)
^ 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.
^ 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.). . New York: McGraw-Hill. Goodman & Gilman's The Pharmacological Basis of Therapeutics ISBN 0-07-142280-3.
^ a b Burger, A.; Yost, W. L. (1948). Journal of the American Chemical Society 70 (6): 2198. doi: 10.1021/ja01186a062.
^ López-Muñoz, F.; Alamo, C. (2009). "Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today". Current pharmaceutical design 15 (14): 1563–1586. doi: 10.2174/138161209788168001. PMID 19442174.
^ Shorter, Edward (2009). . Oxford [Oxfordshire]: Oxford University Press. Before Prozac: the troubled history of mood disorders in psychiatry ISBN 0-19-536874-6.
^ Council on Drugs. Reevaluation of tranylcypromine sulfate. JAMA 189(10): 763-764, 1964.
^ A Double-Blind Study of Tranylcypromine Treatment of Major Anergic Depression
^ Tranylcypromine versus imipramine in anergic bipolar depression Am J Psychiatry 1991;148:910-916.
^ Pharmacotherapy of Borderline Personality Disorder Arch Gen Psychiatry. 1988;45(2):111-119.
^ Efficacy of lithium-tranylcypromine treatment in refractory depression Am J Psychiatry 1985;142:619-623.
^ Treatment of Previously Intractable Depressions With Tranylcypromine and Lithium
^ High dose tranylcypromine therapy for refractory depression Pharmacopsychiatry. 1989 Jan;22(1):21-5.
^ Tranylcypromine Versus Venlafaxine Plus Mirtazapine Following Three Failed Antidepressant Medication Trials for Depression: A STAR*D Report Am J Psychiatry 2006;163:1531-1541.
^ The Clinical State, Sleep and Amine Metabolism of a Tranylcypromine (`Parnate') Addict The British Journal of Psychiatry (1965) 111: 357-364
^ 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.
Rimantadine; Aminotetralins: 7-OH-DPAT
UH-232; Benzazepines: 6-Br-APB
SKF-83,959; Ergolines: Bromocriptine
Pergolide; Dihydrexidine derivatives: 2-OH-NPA
Doxanthrine; Others: A-68,930
see template "Allosteric modulators"
Agonists: Azapirones: Alnespirone
Zalospirone; Antidepressants: Etoperidone
Vortioxetine; Antipsychotics: Aripiprazole
Ziprasidone; Ergolines: Dihydroergotamine
LSD; Tryptamines: 5-CT
Psilocybin; Others: 8-OH-DPAT
Bay R 1531
Antagonists: Antipsychotics: Iloperidone
Sertindole; Beta blockers: Alprenolol
Tertatolol; Others: AV965
Agonists: Lysergamides: Dihydroergotamine
Methysergide; Triptans: Almotriptan
Zolmitriptan; Tryptamines: 5-CT
5-(Nonyloxy)tryptamine; Others: CP-135,807
Antagonists: Lysergamides: Metergoline; Others: Alniditan
Agonists: Phenethylamines: 2C-B
Mescaline; Piperazines: Aripiprazole
TFMPP; Tryptamines: 5-CT
Psilocybin; Others: A-372,159
Antagonists: Atypical antipsychotics: Clorotepine
Zotepine; Typical antipsychotics: Chlorpromazine
Pipamperone; Antidepressants: Agomelatine
Trazodone; Others: Adatanserin
Agonists: Lysergamides: Dihydroergotamine
Methysergide; Tryptamines: 2-Methyl-5-HT
Tryptamine; Others: WAY-181,187
Antagonists: Antidepressants: Amitriptyline
Nortriptyline; Atypical antipsychotics: Aripiprazole
Tiospirone; Typical antipsychotics: Chlorpromazine
Loxapine; Others: BGC20-760
Agonists: Lysergamides: LSD; Tryptamines: 5-CT
Bufotenin; Others: 8-OH-DPAT
Antagonists: Lysergamides: 2-Bromo-LSD
Methysergide; Antidepressants: Amitriptyline
Mianserin; Atypical antipsychotics: Amisulpride
Zotepine; Typical antipsychotics: Chlorpromazine
Pimozide; Others: Butaclamol