Tranylcypromine Systematic ( IUPAC) name (±)- trans-2-phenylcyclopropan-1-amine or (1 R*,2 S*)-2-phenylcyclopropan-1-amine Clinical data Trade names Parnate AHFS/ Drugs.com monograph MedlinePlus a682088 Pregnancy cat. C ( ? AU) ( US) Legal status Prescription Only (S4) ( AU) ℞ -only ( CA) POM ( UK) ℞ -only ( US) ℞ P rescription only Routes Oral Pharmacokinetic data Bioavailability 50% [1 ] Metabolism Liver (by enzymes CYP2A6, CYP2C19, CYP2D6, MAO, and A MAO) B Half-life 2.5 hours [1 ] Excretion Urine, Feces [1 ] Identifiers CAS number 155-09-9 ATC code N06 AF04 PubChem CID 19493 DrugBank DB00752 ChemSpider 18369 UNII 3E3V44J4Z9 ChEMBL CHEMBL1179 Synonyms Transamine Chemical data Formula C 9 H 11 N Mol. mass 133.19 g/mol c1cccc(c1)[C@@H]2C[C@H]2N
Key:AELCINSCMGFISI-DTWKUNHWSA-N (what is this?) (verify) 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 It was withdrawn from the market in February 1964 due to a number of patient deaths involving hypertensive crises with intracranial bleeding.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 worse 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 ] Chemistry [edit ] Synthesis [edit ]
Several methods of
chemical synthesis for tranylcypromine are known.
[3 ] Styrene is reacted with ethyl diazoacetate to give ethyl 2-phenylcyclopropanecarboxylate. Hydrolysis of ethyl 2-phenylcyclopropanecarboxylate in the presence of alkali forms 2-phenylcyclopropanecarboxylic acid. 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 in a Schmidt reaction to realize 2-phenylcyclopropylamine as the product. The four stereoisomers of the final compound are: (1 S,2 R)- trans-2-phenylcyclopropylamine (1 R,2 S)- trans-2-phenylcyclopropylamine (1 R,2 R)- cis-2-phenylcyclopropylamine (1 S,2 S)- cis-2-phenylcyclopropylamine The required racemate of (1 S,2 R)- and (1 R,2 S)- trans-2-phenylcyclopropylamine is separated from (1 R,2 R)- and (1 S,2 S)- cis-2-phenylcyclopropylamine by crystalization with enantiopure tartaric acid, resulting in tranylcypromine.
[16 ] Styrene is reacted with ethyl diazoacetate to give ethyl 2-phenylcyclopropanecarboxylate. Product is 3-4 parts trans isomer and 1-2 parts of cis isomer. Ethyl 2-phenylcyclopropanecarboxylate is epimerized by refluxing in sodium/ethanol. At the end of the reflux, ratio = 95% trans and 5% cis. Further purification through recrystallization at this stage results in pure racemic trans product. Hydrolysis of ethyl 2-phenylcyclopropanecarboxylate in the presence of alkali forms 2-phenylcyclopropanecarboxylic acid. 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). ( DPPA can convert carboxylic acid to azide in one-step Bromadol page) 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 crystalization with the (+)-enantiomer of tartaric acid. 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. ^ Rajadhyaksha, V.J. (1977). "Method of synthesis of trans-2-phenylcyclopropylamine" U.S. Patent 4,016,204
Adamantanes Adenosine antagonists Alkylamines Ampakines Arylcyclohexylamines Benzazepines Cholinergics Convulsants Eugeroics Oxazolines Phenethylamines Phenmetrazines Piperazines Piperidines Pyrrolidines Tropanes Racetams Others
Adamantanes: Amantadine Memantine Rimantadine; Aminotetralins: 7-OH-DPAT 8-OH-PBZI Rotigotine UH-232; Benzazepines: 6-Br-APB Fenoldopam SKF-38,393 SKF-77,434 SKF-81,297 SKF-82,958 SKF-83,959; Ergolines: Bromocriptine Cabergoline Dihydroergocryptine Epicriptine Lisuride LSD Pergolide; Dihydrexidine derivatives: 2-OH-NPA A-86,929 Ciladopa Dihydrexidine Dinapsoline Dinoxyline Doxanthrine; Others: A-68,930 A-77636 A-412,997 ABT-670 ABT-724 Aplindore Apomorphine Aripiprazole Bifeprunox BP-897 CY-208,243 Dizocilpine Etilevodopa Flibanserin Ketamine Melevodopa Modafinil Pardoprunox Phencyclidine PD-128,907 PD-168,077 PF-219,061 Piribedil Pramipexole Propylnorapomorphine Pukateine Quinagolide Quinelorane Quinpirole RDS-127 Ro10-5824 Ropinirole Rotigotine Roxindole Salvinorin A SKF-89,145 Sumanirole Terguride Umespirone WAY-100,635
Agonists: Azapirones: Alnespirone Binospirone Buspirone Enilospirone Eptapirone Gepirone Ipsapirone Perospirone Revospirone Tandospirone Tiospirone Umespirone Zalospirone; Antidepressants: Etoperidone Nefazodone Trazodone Vortioxetine; Antipsychotics: Aripiprazole Asenapine Clozapine Quetiapine Ziprasidone; Ergolines: Dihydroergotamine Bromocriptine Ergotamine Lisuride Methysergide LSD; Tryptamines: 5-CT 5-MeO-DMT 5-MT Bufotenin DMT Indorenate Psilocin Psilocybin; Others: 8-OH-DPAT Adatanserin Bay R 1531 Befiradol BMY-14802 Cannabidiol Dimemebfe Ebalzotan Eltoprazine F-11,461 F-12,826 F-13,714 F-14,679 F-15,063 F-15,599 Flesinoxan Flibanserin Lesopitron LY-293,284 LY-301,317 MKC-242 Naluzotan NBUMP Osemozotan Oxaflozane Pardoprunox Piclozotan Rauwolscine Repinotan Roxindole RU-24,969 S 14,506 S-14,671 S-15,535 Sarizotan SSR-181,507 Sunepitron U-92,016-A Urapidil Vilazodone Xaliproden Yohimbine Antagonists: Antipsychotics: Iloperidone Risperidone Sertindole; Beta blockers: Alprenolol Cyanopindolol Iodocyanopindolol Oxprenolol Pindobind Pindolol Propranolol Tertatolol; Others: AV965 BMY-7,378 CSP-2503 Dotarizine Flopropione GR-46611 Isamoltane Lecozotan Mefway Metitepine/Methiothepin MPPF NAN-190 Robalzotan S-15535 SB-649,915 SDZ 216-525 Spiperone Spiramide Spiroxatrine UH-301 WAY-100,135 WAY-100,635 Xylamidine Agonists: Lysergamides: Dihydroergotamine Methysergide; Triptans: Almotriptan Avitriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Sumatriptan Zolmitriptan; Tryptamines: 5-CT 5-Ethyl-DMT 5-MT 5-(Nonyloxy)tryptamine; Others: CP-135,807 Bromocriptine CP-286,601 GR-46611 L-694,247 L-772,405 PNU-109,291 PNU-142633 Antagonists: Lysergamides: Metergoline; Others: Alniditan BRL-15,572 Elzasonan GR-127,935 Ketanserin LY-310,762 LY-367,642 LY-456,219 LY-456,220 Metitepine/Methiothepin Ritanserin Yohimbine Ziprasidone
Agonists: Phenethylamines: 2C-B 2C-E 2C-I 2C-T-2 2C-T-7 2C-T-21 DOB DOC DOI DOM MDA MDMA Mescaline; Piperazines: Aripiprazole mCPP TFMPP; Tryptamines: 5-CT 5-MeO-α-ET 5-MeO-α-MT 5-MeO-DET 5-MeO-DiPT 5-MeO-DMT 5-MeO-DPT 5-MT α-ET α-Methyl-5-HT α-MT Bufotenin DET DiPT DMT DPT Psilocin Psilocybin; Others: A-372,159 AL-38022A Alstonine Bromocriptine CP-809,101 Dimemebfe Lorcaserin Medifoxamine MK-212 Org 12,962 ORG-37,684 Oxaflozane PHA-57378 PNU-22394 PNU-181731 Ro60-0175 Ro60-0213 Vabicaserin WAY-629 WAY-161,503 YM-348 Antagonists: Atypical antipsychotics: Clorotepine Clozapine Iloperidone Melperone Olanzapine Paliperidone Quetiapine Risperidone Sertindole Ziprasidone Zotepine; Typical antipsychotics: Chlorpromazine Loxapine Pimozide Pipamperone; Antidepressants: Agomelatine Amitriptyline Amoxapine Aptazapine Etoperidone Fluoxetine Mianserin Mirtazapine Nefazodone Nortriptyline Tedatioxetine Trazodone; Others: Adatanserin CEPC Cinanserin Cyproheptadine Deramciclane Dotarizine Eltoprazine Esmirtazapine FR-260,010 Ketanserin Ketotifen Latrepirdine Metitepine/Methiothepin Methysergide Pizotifen Ritanserin RS-102,221 S-14,671 SB-200,646 SB-206,553 SB-221,284 SB-228,357 SB-242,084 SB-243,213 SDZ SER-082 Xylamidine
Agonists: Lysergamides: Dihydroergotamine Ergotamine Lisuride LSD Mesulergine Metergoline Methysergide; Tryptamines: 2-Methyl-5-HT 5-BT 5-CT 5-MT Bufotenin E-6801 E-6837 EMD-386,088 EMDT LY-586,713 N-Methyl-5-HT Tryptamine; Others: WAY-181,187 WAY-208,466 Antagonists: Antidepressants: Amitriptyline Amoxapine Clomipramine Doxepin Mianserin Nortriptyline; Atypical antipsychotics: Aripiprazole Asenapine Clorotepine Clozapine Fluperlapine Iloperidone Olanzapine Tiospirone; Typical antipsychotics: Chlorpromazine Loxapine; Others: BGC20-760 BVT-5182 BVT-74316 Cerlapirdine EGIS-12,233 GW-742,457 Ketanserin Latrepirdine Lu AE58054 Metitepine/Methiothepin MS-245 PRX-07034 Ritanserin Ro04-6790 Ro 63-0563 SB-258,585 SB-271,046 SB-357,134 SB-399,885 SB-742,457 Agonists: Lysergamides: LSD; Tryptamines: 5-CT 5-MT Bufotenin; Others: 8-OH-DPAT AS-19 Bifeprunox E-55888 LP-12 LP-44 RU-24,969 Sarizotan Antagonists: Lysergamides: 2-Bromo-LSD Bromocriptine Dihydroergotamine Ergotamine Mesulergine Metergoline Methysergide; Antidepressants: Amitriptyline Amoxapine Clomipramine Imipramine Maprotiline Mianserin; Atypical antipsychotics: Amisulpride Aripiprazole Asenapine Clorotepine Clozapine Olanzapine Risperidone Sertindole Tiospirone Ziprasidone Zotepine; Typical antipsychotics: Chlorpromazine Loxapine; Pimozide; Others: Butaclamol EGIS-12,233 Ketanserin LY-215,840 Metitepine/Methiothepin Ritanserin SB-258,719 SB-258,741 SB-269,970 SB-656,104 SB-656,104-A SB-691,673 SLV-313 SLV-314 Spiperone SSR-181,507 Vortioxetine