Chemical Properties
white to light beige powder or chunks
Uses
Antidepressant;MAO inhibitor
Uses
Non-selective MAO-A/B inhibitor
Uses
As with the MAO inhibitor drugs described above, tranylcypromine is also used for
depressions that do not respond to other drugs.
Definition
ChEBI: (1R,2S)-tranylcypromine hydrochloride is a hydrochloride obtained by combining (1R,2S)-tranylcypromine with one equivalent of hydrochloric acid. It contains a (1R,2S)-tranylcypromine(1+). It is an enantiomer of a (1S,2R)-tranylcypromine hydrochloride.
General Description
A cell-permeable phenylcyclopropylamine that inhibits the monoamine oxidase and histone demethylase activities, respectively, of MAO A/B (
Ki = 101.9 and 16.0 M, respectively) and LSD1/2 (
Ki = 242.7 and 180.0 M, respectively), four members of a flavin-dependent amine oxidase family enzymes, by a covalent adduct formation with the enzyme-bound FAD. In addition to preventing LSD1-CoREST (Corepressor of RE1-Silencing Transcription factor) complex-mediated H3K4 demethylation (IC
50<2 M), TCP also inhibits LSD1-HCF-1 (Host Cell Factor-1) complex-mediated H3K9 demethylase activity, which is demonstrated to be an essential mechanism for the replication and latent infection of the α-herpesviruses HSV and VZV. The combined treatment of 2 M TCP and 10 M CHIR99061 is reported to enable the reprogramming of
Oct4/
Klf4-transduced primary HNEKs (Human Neonatal Epidermal Keratinocytes) into iPS (induced Pluripotent Stem) cells, albeit at a 100-time lower efficiency as seen in cultures transduced with 4-TFs (
Oct44,
Klf4,
Sox2, and c-
Myc).
Biological Activity
Irreversible inhibitor of lysine-specific demethylase 1 (LSD1/BHC110) and monoamine oxidase (MAO) (K i values are 242, 102 and 16 μ M for LSD1, MAO-A and MAO-B respectively). Inhibits histone demethylation.
Clinical Use
MAOI antidepressant
Synthesis
Tranylcypromine, (?à)-trans-2-phenylcyclopropylamine (7.2.10),
differs from the drugs described above in that it is not a derivative of hydrazine. It is
synthesized from the ethyl ester of 2-phenylcyclopropan carboxylic acid (7.2.7), which is synthesized by the reaction of styrene with ethyl diazoacetate. 2-phenylcyclopropancarboxylic acid ethyl ester (7.2.7) is hydrolyzed by alkali to 2-phenylcyclopropancarboxylic acid (7.2.8) and the trans-isomer is separated for further reactions. The reaction
of the trans-isomer with thionyl chloride gives trans-2-phenylcyclopropancarboxylic
acid chloride (7.2.9), which upon reaction with sodium azide gives the respective acid
azide, which undergoes Curtius rearrangement to the transcyclopropylamine (7.2.10)
[48,49].
Drug interactions
Potentially hazardous interactions with other drugs
Alcohol: some alcoholic and dealcoholised drinks
contain tyramine which can cause hypertensive crisis.
Alpha-blockers: enhanced hypotensive effect; avoid
with indoramin.
Analgesics: CNS excitation or depression with
pethidine, other opioids and nefopam - avoid;
increased risk of serotonergic effects and convulsions
with tramadol - avoid.
Antibacterials: increased risk of hypertension and
CNS excitation with linezolid and tedizolid - avoid
for at least 2 weeks after stopping MAOIs.
Antidepressants: enhancement of CNS effects and
toxicity. Care with all antidepressants including drug
free periods when changing therapies.
Antidiabetics: possibly enhanced hypoglycaemic
effect.
Antiepileptics: antagonism of anticonvulsant effect;
avoid carbamazepine with or within 2 weeks of
MAOIs.
Antihypertensives: enhanced hypotensive effect.
Antimalarials: avoid with artemether/lumefantrine
and piperaquine with artenimol.
Antipsychotics: effects enhanced by clozapine.
Anxiolytics: avoid buspirone with or within 2 weeks
of MAOIs.
Atomoxetine: avoid concomitant use and for 2 weeks
after use; increased risk of convulsions.
Bupropion: avoid with or for 2 weeks after MAOIs.
Dapoxetine: risk of hypertensive crisis - avoid.
Diuretics: enhanced hypotensive effect; avoid with
indoramin.
Dopaminergics: avoid with entacapone, safinamide
and tolcapone; hypertensive crisis with levodopa and
rasagiline - avoid for at least 2 weeks after stopping
MAOI; hypotension with selegiline.
5HT1
agonist: risk of CNS toxicity with
sumatriptan, rizatriptan and zolmitriptan - avoid
sumatriptan and rizatriptan for 2 weeks after MAOI.
Metaraminol: risk of hypertensive crisis - avoid for
at least 2 weeks after stopping MAOIs.
Methyldopa: avoid concomitant use.
Opicapone: avoid concomitant use.
Sympathomimetics: hypertensive crisis with
sympathomimetics - avoid.
Tetrabenazine: risk of CNS excitation and
hypertension avoid.
Metabolism
Tranylcypromine undergoes considerable hepatic metabolism, including breakdown of the side chain and probably conjugation. Excretion is renal mainly as metabolites.
storage
room temperature (desiccate)
