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; category	AU: B2; US: C (Risk not ruled out); ;
Routes of; administration	Oral
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: ℞-only; ℞ (Prescription only);
Pharmacokinetic data
Bioavailability	50%
Metabolism	Liver (by enzymes CYP2A6, CYP2C19, CYP2D6, MAOA, and MAOB)
Biological half-life	2.5 hours
Excretion	Urine, Feces
Identifiers
CAS Number	155-09-9
ATC code	N06AF04 (WHO)
PubChem	CID 19493
DrugBank	DB00752
ChemSpider	18369
UNII	3E3V44J4Z9
ChEBI	CHEBI:9652
ChEMBL	CHEMBL1179
Synonyms	Transamine
Chemical data
Formula	C9H11N
Molar mass	133.19 g/mol
	SMILES c1cccc(c1)[C@@H]2C[C@H]2N ;
	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 ; Key:AELCINSCMGFISI-DTWKUNHWSA-N ;
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WordNet

an antidepressant drug that is a monoamine oxidase inhibitor; administered as a sulfate

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/03/14 14:34:59」(JST)

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Tranylcypromine (INN, USAN, BAN) (brand names: Parnate, Jatrosom (which is a brand solely sold in Germany)) is a monoamine oxidase inhibitor (MAOI)—it is a nonselective 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.

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.

Contraindications

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

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

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.^[3]

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 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.^[4]

Tranylcypromine inhibition of lysine-specific demethylase 1 (LSD1) suppressed herpes lytic infection, subclinical shedding, and reactivation from latency in animals.^[5]

Tranylcypromine has also been found to inhibit prostacyclin synthase.^{[citation needed]}

History

Tranylcypromine was originally developed as an analog of amphetamine.^[1] Although it was first synthesized in 1948,^[6] 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 it might have a more acceptable therapeutic index than previous MAOIs.^[7]

The drug was introduced by Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961.^[8] 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.^[9]

References

^ ^a ^b ^c ^d ^e ^f Williams, David A. (2007). "Antidepressants". In Foye, William O.; Lemke, Thomas L.; Williams, David A. Foye's Principles of Medicinal Chemistry. Hagerstwon, USA: 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.). Goodman & Gilman's The Pharmacological Basis of Therapeutics. New York: McGraw-Hill. ISBN 0-07-142280-3.
^ Le Gassicke, J; Ashcroft, GW; Eccleston, D; Evans, JI; Oswald, I; Ritson, EB (1 April 1965). "The Clinical State, Sleep and Amine Metabolism of a Tranylcypromine (`Parnate') Addict". The British Journal of Psychiatry 111 (473): 357–364. doi:10.1192/bjp.111.473.357.
^ Lee, MG; Wynder, C; Schmidt, DM; McCafferty, DG; Shiekhattar, R (June 2006). "Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications.". Chemistry & Biology 13 (6): 563–7. doi:10.1016/j.chembiol.2006.05.004. PMID 16793513.
^ Hill, Sci Transl Med 6:265ra169 2014 PMID 25473037.
^ Burger, A; Yost, WL. "Arylcycloalkylamines. I. 2-Phenylcyclopropylamine". Journal of the American Chemical Society 70 (6): 2198–2201. 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): 1563–86. doi:10.2174/138161209788168001. PMID 19442174.
^ Shorter, Edward (2009). Before Prozac: the troubled history of mood disorders in psychiatry. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-536874-6.
^ ATCHLEY, DW (September 1964). "Reevaluation of Tranylcypromine Sulfate(Parnate Sulfate)". JAMA 189: 763–4. doi:10.1001/jama.1964.03070100057011. PMID 14174054.

UpToDate Contents

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1. 成人におけるうつ病治療としてのモノアミン酸化酵素阻害剤（MAOI） monoamine oxidase inhibitors maois for treating depressed adults
2. 成人における抗うつ剤：薬剤の変更および投与中止 antidepressant medication in adults switching and discontinuing medication
3. 妊娠中の抗うつ薬のリスク：選択的セロトニン再取り込み阻害剤以外の薬剤 risks of antidepressants during pregnancy drugs other than selective serotonin reuptake inhibitors
4. 社会不安障害の薬物療法 pharmacotherapy for social anxiety disorder
5. 成人における単極性うつ病：難治性うつ病の治療 unipolar depression in adults treatment of resistant depression

English Journal

An improved substrate cocktail for assessing direct inhibition and time-dependent inhibition of multiple cytochrome P450s.

Chen ZH1,2, Zhang SX3, Long N3, Lin LS3, Chen T3, Zhang FP3, Lv XQ3, Ye PZ3, Li N4, Zhang KZ3.
Acta pharmacologica Sinica.Acta Pharmacol Sin.2016 May;37(5):708-18. doi: 10.1038/aps.2016.10. Epub 2016 Apr 11.
AIM: The substrate cocktail is frequently used to evaluate cytochrome P450 (CYP) enzyme-mediated drug interactions and potential interactions among the probe substrates. Here, we re-optimized the substrate cocktail method to increase the reliability and accuracy of screening for candidate compounds
PMID 27063220

The histone demethylase LSD1 is a novel oncogene and therapeutic target in oral cancer.

Wang Y1, Zhu Y1, Wang Q1, Hu H1, Li Z2, Wang D3, Zhang W4, Qi B4, Ye J3, Wu H3, Jiang H3, Liu L5, Yang J2, Cheng J6.
Cancer letters.Cancer Lett.2016 Apr 28;374(1):12-21. doi: 10.1016/j.canlet.2016.02.004. Epub 2016 Feb 9.
The histone demethylase LSD1 functions as a key pro-oncogene and attractive therapeutic target in human cancer. Here we sought to interrogate the oncogenic roles of LSD1 in OSCC tumorigenesis and therapeutic intervention by integrating chemical-induced OSCC model, genetic and pharmacological loss-of
PMID 26872725

Inhibitors of LSD1 as a potential therapy for acute myeloid leukemia.

Przespolewski A1, Wang ES1.
Expert opinion on investigational drugs.Expert Opin Investig Drugs.2016 Apr 21:1-10. [Epub ahead of print]
INTRODUCTION: Epigenetic dysregulation plays a critical role in the pathogenesis of acute myeloid leukemia (AML). Alterations in histone methylation lead to aberrant silencing of expression of multiple genes involved in tumor suppression and cell cycling, resulting in myeloid maturation arrest and p
PMID 27077938

Japanese Journal

発達期の一時的なモノアミン代謝異常はマウスの成長後の情動性を変化させる

環境と経営 : 静岡産業大学論集 23(1), 41-55, 2017-06
NAID 120006373600

Novel Tranylcypromine/Hydroxylcinnamic Acid Hybrids as Lysine-Specific Demethylase 1 Inhibitors with Potent Antitumor Activity

Chemical and Pharmaceutical Bulletin 63(11), 882-889, 2015
NAID 130005105728

Measurement of lysine-specific demethylase-1 activity in the nuclear extracts by flow-injection based time-of-flight mass spectrometry

Journal of Clinical Biochemistry and Nutrition advpub(0), 2015
NAID 130004879396

Related Pictures

[Foye.27s-1] ^ ^a ^b ^c ^d ^e ^f Williams, David A. (2007). "Antidepressants". In Foye, William O.; Lemke, Thomas L.; Williams, David A. Foye's Principles of Medicinal Chemistry. Hagerstwon, USA: Lippincott Williams & Wilkins. pp. 590–1. ISBN 0-7817-6879-9.

[G.26G-2] 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 0-07-142280-3.

[3] Le Gassicke, J; Ashcroft, GW; Eccleston, D; Evans, JI; Oswald, I; Ritson, EB (1 April 1965). "The Clinical State, Sleep and Amine Metabolism of a Tranylcypromine (`Parnate') Addict". The British Journal of Psychiatry 111 (473): 357–364. doi:10.1192/bjp.111.473.357.

[4] Lee, MG; Wynder, C; Schmidt, DM; McCafferty, DG; Shiekhattar, R (June 2006). "Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications.". Chemistry & Biology 13 (6): 563–7. doi:10.1016/j.chembiol.2006.05.004. PMID 16793513.

[5] Hill, Sci Transl Med 6:265ra169 2014 PMID 25473037.

[6] Burger, A; Yost, WL. "Arylcycloalkylamines. I. 2-Phenylcyclopropylamine". Journal of the American Chemical Society 70 (6): 2198–2201. doi:10.1021/ja01186a062.

[7] López-Muñoz, F; Alamo, C (2009). "Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today.". Current Pharmaceutical Design 15 (14): 1563–86. doi:10.2174/138161209788168001. PMID 19442174.

[isbn0-19-536874-6-8] Shorter, Edward (2009). Before Prozac: the troubled history of mood disorders in psychiatry. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-536874-6.

[9] ATCHLEY, DW (September 1964). "Reevaluation of Tranylcypromine Sulfate(Parnate Sulfate)". JAMA 189: 763–4. doi:10.1001/jama.1964.03070100057011. PMID 14174054.

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