Tranylcypromine (Parnate, Jatrosom) is a drug A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage of the substituted phenethylamine The substituted phenethylamines are a family of chemical compounds that contain the 2-phenylethylamine chemical structure and also have additional modifications at the phenyl ring, sidechain, and/or amino group. Many of them are psychoactive drugs, including stimulants, psychedelics, and entactogens, which exert their effects primarily through and amphetamine The substituted amphetamines are a chemical class of stimulants, entactogens, hallucinogens, and other psychoactive drugs. They feature a phenethylamine core with a methyl group attached to the alpha carbon resulting in amphetamine, along with additional substitutions classes which acts as a monoamine oxidase inhibitor Monoamine oxidase inhibitors are a class of powerful antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression, and have also shown efficacy in smoking cessation (MAOI)—it is a non-selective and irreversible inhibitor Enzyme inhibitors are molecules that bind to enzymes and decrease their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides. Not all molecules that bind to enzymes are inhibitors; enzyme activators bind to enzymes and of the enzyme Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at significant rates. Since enzymes are selective for their monoamine oxidase Monoamine oxidases (EC 1.4.3.4) are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was first discovered by Mingte Lee and Sam Bedford et. al. in the ovary, and who named the enzyme tyramine oxidase. They belong to protein family of (MAO).^[1] It is used as an antidepressant An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. Drugs including the monoamine oxidase inhibitors , tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), and and anxiolytic An anxiolytic is a drug used for the treatment of symptoms of anxiety. Anxiolytics have been shown to be useful in the treatment of anxiety disorders agent in the clinical A clinic is a small private or public health facility that is devoted to the care of outpatients, often in a community, in contrast to larger hospitals, which also treat inpatients. Some grow to be institutions as large as major hospitals, whilst retaining the name clinic. These are often associated with a hospital or medical school treatment Therapy , or treatment, is the attempted remediation of a health problem, usually following a diagnosis. In the medical field, it is synonymous with the word "treatment". Among psychologists, the term may refer specifically to psychotherapy or "talk therapy" of mood A mood disorder is the term given for a group of diagnoses in the Diagnostic and Statistical Manual of Mental Disorders classification system where a disturbance in the person's mood is hypothesized to be the main underlying feature. The classification is known as mood (affective) disorders in ICD 10 and anxiety disorders Anxiety disorders are blanket terms covering several different forms of abnormal and pathological fear and anxiety which only came under the aegis of psychiatry at the very end of the 19th century. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders. Recent surveys have found that as many as 18% of Americans may, respectively.

History

Tranylcypromine was originally developed as an analogue In chemistry, structural analogs , also known as chemical analogs or simply analogs, are compounds in which one or more atoms, functional groups, or substructures have been replaced with different atoms, groups, or substructures. Despite a high chemical similarity, structural analogs are not necessarily functional analogs and can have very of amphetamine.^[1] Although it was first synthesized in 1948,^[2] its MAOI action was not discovered until 1959. Precisely because tranylcypromine was not, like isoniazid Isoniazid , also known as isonicotinylhydrazine (INH), is an organic compound that is the first-line antituberculosis medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis. Isoniazid is never used on its own to treat active tuberculosis because resistance and iproniazid Iproniazid is a hydrazine drug used as an antidepressant. It acts as an irreversible and nonselective monoamine oxidase inhibitor (MAOI). Though it has been widely discontinued in most of the world, it is still used in France, a hydrazine Hydrazine is an inorganic chemical compound with the formula N2H4. It is a colourless liquid with an ammonia-like odor and is derived from the same industrial chemistry processes that manufacture ammonia. However, hydrazine has physical properties that are more similar to those of water derivative, its clinical interest increased enormously, as it was thought that it might have a more acceptable therapeutic index The therapeutic index , is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death. Quantitatively, it is the ratio given by the lethal dose divided by the therapeutic dose. A therapeutic index is the lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective than previous MAOIs.^[3]

The drug was introduced by Smith, Kline & French in the United Kingdom The United Kingdom of Great Britain and Northern Ireland[note 7] is a sovereign state located off the northwestern coast of continental Europe. It is an island country, spanning an archipelago including Great Britain, the northeastern part of the island of Ireland, and many small islands. Northern Ireland is the only part of the UK with a land in 1960 and approval in the United States ^ b. English is the de facto language of American government and the sole language spoken at home by 80% of Americans age five and older. Spanish is the second most commonly spoken language soon followed in 1961.^[4] 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]

Clinical use

Tranylcypromine is indicated primarily for the treatment of major depressive disorder Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities. The term "major depressive disorder" was selected by the American Psychiatric Association to designate this symptom cluster as a mood disorder without melancholia Melancholia , also lugubriousness, from the Latin lugere, to mourn; moroseness, from the Latin morosus, self-willed, fastidious habit; wistfulness, from old English wist: intent, or saturnine, (see Saturn), in contemporary usage, is a mood disorder of non-specific depression, characterized by low levels of enthusiasm and eagerness for activity. It is generally used to remedy various types of mood A mood disorder is the term given for a group of diagnoses in the Diagnostic and Statistical Manual of Mental Disorders classification system where a disturbance in the person's mood is hypothesized to be the main underlying feature. The classification is known as mood (affective) disorders in ICD 10 and anxiety disorders Anxiety disorders are blanket terms covering several different forms of abnormal and pathological fear and anxiety which only came under the aegis of psychiatry at the very end of the 19th century. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders. Recent surveys have found that as many as 18% of Americans may, typically as a last resort only after conventional antidepressants have been tried without success. It also has some off-label Off-label use is the practice of prescribing pharmaceuticals for an unapproved indication. In the United States, the Food and Drug Administration Center for Drug Evaluation and Research reviews a company's New Drug Application (NDA) for data from clinical trials to see if the results support the drug for a specific use or indication. If satisfied uses, such as in the treatment of post-traumatic stress disorder Posttraumatic stress disorder is a severe anxiety disorder that can develop after exposure to any event which results in psychological trauma. This event may involve the threat of death to oneself or to someone else, or to one's own or someone else's physical, sexual, or psychological integrity, overwhelming the individual's ability to cope. As an (PTSD).

Contraindications

Therapeutic contraindications A contraindication is a condition or factor that speaks against a certain measure. It is mostly used in medicine, with regard to factors that increase the risks involved in using a particular drug, carrying out a medical procedure, or engaging in a particular activity of tranylcypromine include:

• Cardiovascular Heart disease or cardiovascular diseases is the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system (as used in MeSH C14), it is usually used to refer to those related to atherosclerosis (arterial disease). These conditions have similar causes, or cerebrovascular disease Cerebrovascular disease is a group of brain dysfunctions related to disease of the blood vessels supplying the brain. Hypertension is the most important cause; it damages the blood vessel lining, endothelium, exposing the underlying collagen where platelets aggregate to initiate a repairing process which is not always complete and perfect
• Drug abuse Substance abuse, also known as drug abuse, refers to a maladaptive pattern of use of a substance that is not considered dependent. The term "drug abuse" does not exclude dependency, but is otherwise used in a similar manner in nonmedical contexts. The terms have a huge range of definitions related to taking a psychoactive drug or (due to the potential for interactions A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind . However, interactions may also exist between drugs & foods (drug-food interactions), as well as with certain agents, especially stimulants Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others. Due to their effects typically having an "up" quality to them, stimulants are also occasionally referred to as &)
• Low body weight Although some people prefer the less-ambiguous term body mass, the term body weight is overwhelmingly used in daily English speech as well as in the contexts of biological and medical sciences to describe the mass of an organism's body. Body weight is measured in kilograms throughout the world, although in some countries people more often measure, anorexia Anorexia (deriving from the Greek "α-" (a(n)-, a prefix that denotes absence) + "όρεξη" (orexe) = appetite) is the decreased sensation of appetite. While the term in non-scientific publications is often used interchangeably with anorexia nervosa, many possible causes exist for a decreased appetite, some of which may be, or eating disorders Eating disorders are a group of conditions characterized by abnormal eating habits that may involve either insufficient or excessive food intake to the detriment of an individual's physical and emotional health, binge eating disorder, bulimia nervosa, anorexia nervosa being the most common specific forms in the United States, Primarily thought of of the sort
• Pheochromocytoma A phaeochromocytoma or pheochromocytoma, is a neuroendocrine tumor of the medulla of the adrenal glands (originating in the chromaffin cells), or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually adrenaline (epinephrine) if in the adrenal gland and not extra-adrenal, and
• Pre-existing and chronic headaches A headache or cephalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the pain-sensitive structures around the brain. Several areas of the or migraines Migraine is a neurological syndrome characterized by altered bodily perceptions, severe headaches, and nausea. Physiologically, the migraine headache is a neurological condition more common to women than to men. The word migraine was borrowed from Old French migraigne . The French term derived from a vulgar pronunciation of the Late Latin word
• Psychosis Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality". People suffering from psychosis are described as psychotic such as schizophrenia Schizophrenia is a serious mental illness characterized by a disintegration of the process of thinking, of contact with reality, and of emotional responsiveness. It most commonly manifests as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking with significant social or occupational dysfunction. Onset of or bipolar disorder Bipolar disorder or manic–depressive disorder is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood and one or more depressive episodes. The elevated moods are clinically referred to as mania or, if milder, hypomania

Dietary restrictions

Foods high in endogenous Endogenous substances are those that originate from within an organism, tissue, or cell . Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates. Their proviruses remain in the genome and are passed on to the next generation monoamine Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group that is connected to an aromatic ring by a two-carbon chain . All monoamines are derived from aromatic amino acids like phenylalanine, tyrosine, tryptophan, and the thyroid hormones by the action of aromatic amino acid decarboxylase enzymes precursors or exogenous Exogenous (from the Greek words "exo" and "gen", meaning "outside" and "production") refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system monoamine compounds A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together in a defined spatial arrangement by chemical bonds may cause adverse reactions. The most common example of this, is the hypertensive crisis A hypertensive emergency is severe hypertension with acute impairment of an organ system (especially the central nervous system, cardiovascular system and/or the renal system) and the possibility of irreversible organ-damage. In case of a hypertensive emergency, the blood pressure should be lowered aggressively over minutes to hours with an caused by the ingestion of tyramine Tyramine is a naturally-occurring monoamine compound and trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine (dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline)) releasing agent. Notably, however, it is unable to cross the blood-brain-barrier (BBB), resulting in only non-psychoactive peripheral, which is found in foods like aged cheeses, cured meats, tofu Tofu , or bean curd is a food made by coagulating soy milk, and then pressing the resulting curds into soft white blocks. It is of Chinese origin, and part of East Asian and Southeast Asian cuisine such as Chinese, Japanese, Korean, Indonesian, Vietnamese, and others. There are many different varieties of tofu, including fresh tofu and tofu that and certain red wines Wine is an alcoholic beverage typically made of fermented grape juice. The natural chemical balance of grapes is such that they can ferment without the addition of sugars, acids, enzymes or other nutrients. Wine is produced by fermenting crushed grapes using various types of yeast. Yeast consumes the sugars found in the grapes and converts them. Some, such as yeast extracts like Bovril and Marmite, 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).

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

As mentioned above, tranylcypromine acts as a nonselective and irreversible monoamine oxidase inhibitor. 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 1/10th 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.^[6]

Chemistry

Synthesis

Several methods of chemical synthesis for tranylcypromine are known.

Traditional:^[2]

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 steroisomers 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:^[7]

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} Williams, David A. (2007). "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} Burger, A.; Yost, W. L. (1948). Journal of the American Chemical Society 70: 2198. doi:10.1021/ja01186a062.
3. ^ 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.
4. ^ 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.
5. ^ Council on Drugs. Reevaluation of tranylcypromine sulfate. JAMA 189(10): 763-764, 1964.
6. ^ 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.
7. ^ Rajadhyaksha, V.J. (1977). "Method of synthesis of trans-2-phenylcyclopropylamine" U.S. Patent 4,016,204

Categories: Monoamine oxidase inhibitors | Phenethylamines | GlaxoSmithKline

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