Tranylcypromine
Encyclopedia
Tranylcypromine is a drug
of the substituted phenethylamine
and amphetamine
classes which acts as a monoamine oxidase inhibitor
(MAOI)—it is a non-selective
and irreversible inhibitor
of the enzyme
monoamine oxidase
(MAO). It is used as an antidepressant
and anxiolytic
agent in the clinic
al treatment
of mood
and anxiety disorder
s, respectively.
of amphetamine
. Although it was first synthesized in 1948, 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 that it might have a more acceptable therapeutic index
than previous MAOIs.
The drug was introduced by Smith, Kline & French in the United Kingdom
in 1960 and approval in the United States
soon followed 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 It was withdrawn from the market in February 1964 due to a number of patient deaths involving hypertensive crises with intracranial bleeding.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.
, and the availability of newer and safer (although not necessarily more efficacious) antidepressants. Tranylcypromine is indicated primarily for the treatment of major depressive disorder, and can also be used in the management of various mood
and anxiety disorder
s, typically as a last resort after conventional antidepressants have been tried without success.
. However, at normal dosages, tranylcypromine proved no more effective than venlafaxine and mirtazapine in treatment-resistant depression, and was associated with worse side effects.
s of tranylcypromine include:
monoamine precursors or exogenous
monoamine compound
s may cause adverse reactions. The most common example of this, is the hypertensive crisis caused by the ingestion of tyramine
, which is found in foods like aged cheeses, cured meats, tofu
and certain red wines. Some, such as yeast extract
s, contain enough tyramine to be potentially fatal in a single serving. Spoiled food is also likely to contain dangerous levels of tyramine.
s 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 hydrazine
s, 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
.
, 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.
and dopamine
releasing agent
(NDRA) with approximately 1/10 the potency
of amphetamine
.
As a result of these actions, tranylcypromine considerably boosts the concentration
s and activity of the monoamine neurotransmitter
s serotonin
and dopamine
, along with paradoxical and varying effects on norepinephrine
and epinephrine
. It increases the levels of the trace amine
s phenethylamine
, tyramine
, octopamine
, and tryptamine
as well. It is believed to be tranylcypromine's action on these neurochemical
s 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.
for tranylcypromine are known.
Traditional:
Modern:
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.In pharmacology, a...
of the substituted phenethylamine
Substituted phenethylamine
The substituted phenethylamines are chemical compounds with the 2-phenethylamine chemical structure modified at the phenyl ring, sidechain, and/or amino group. Some of them are psychoactive drugs, including stimulants, psychedelics, opioids, and entactogens, which exert their effects primarily...
and amphetamine
Substituted amphetamine
Substituted amphetamines are a chemical class of stimulants, entactogens, hallucinogens, and other 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 inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
(MAOI)—it is a non-selective
Binding selectivity
Binding selectivity refers to the differing affinities with which different ligands bind to a substrate forming a complex. A selectivity coefficient is the equilibrium constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate...
and irreversible inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases 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...
of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
monoamine oxidase
Monoamine oxidase
L-Monoamine oxidases 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 originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...
(MAO). It is used as an antidepressant
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. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
and anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
agent in the clinic
Clinic
A clinic is a health care facility that is primarily devoted to the care of outpatients...
al treatment
Therapy
This is a list of types of therapy .* Adventure therapy* Animal-assisted therapy* Aquatic therapy* Aromatherapy* Art and dementia* Art therapy* Authentic Movement* Behavioral therapy* Bibliotherapy* Buteyko Method* Chemotherapy...
of mood
Mood disorder
Mood disorder is the term designating 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...
and anxiety disorder
Anxiety disorder
Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Conditions now considered anxiety disorders only came under the aegis of psychiatry at the end of the 19th century. Gelder, Mayou & Geddes explains that anxiety disorders are...
s, respectively.
History
Tranylcypromine was originally developed as an analogueAnalog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
. Although it was first synthesized in 1948, its MAOI action was not discovered until 1959. Precisely because tranylcypromine was not, like isoniazid
Isoniazid
Isoniazid , also known as isonicotinylhydrazine , 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 by inhibiting its mycolic acid...
and iproniazid
Iproniazid
Iproniazid is a hydrazine drug used as an antidepressant. It acts as an irreversible and nonselective monoamine oxidase inhibitor . Though it has been widely discontinued in most of the world, it is still used in France.- History :Iproniazid was the first antidepressant ever marketed...
, a hydrazine
Hydrazine
Hydrazine is an inorganic compound with the formula N2H4. It is a colourless flammable liquid with an ammonia-like odor. Hydrazine is highly toxic and dangerously unstable unless handled in solution. Approximately 260,000 tons are manufactured annually...
derivative, its clinical interest increased enormously, as it was thought that it might have a more acceptable therapeutic index
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 or toxicity ....
than previous MAOIs.
The drug was introduced by Smith, Kline & French in the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
in 1960 and approval in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
soon followed 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.
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 interactionsDrug interaction
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...
, and the availability of newer and safer (although not necessarily more efficacious) antidepressants. Tranylcypromine is indicated primarily for the treatment of major depressive disorder, and can also be used in the management of various mood
Mood disorder
Mood disorder is the term designating 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...
and anxiety disorder
Anxiety disorder
Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Conditions now considered anxiety disorders only came under the aegis of psychiatry at the end of the 19th century. Gelder, Mayou & Geddes explains that anxiety disorders are...
s, typically as a last resort after conventional antidepressants have been tried without success.
Effectiveness
Tranylcypromine is highly effective in the treatment of anergic depression in comparison to placebo. In comparison to imipramine, tranylcypromine has been shown to be more effective in anergic bipolar depression, and results in fewer patients leaving treatment. As contrasted with 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 treatment-resistant depression, with, or, at unusually high dosages, without, lithiumLithium pharmacology
Lithium pharmacology refers to use of the lithium ion, Li+, as a drug. A number of chemical salts of lithium are used medically as a mood stabilizing drug, primarily in the treatment of bipolar disorder, where they have a role in the treatment of depression and particularly of mania, both acutely...
. However, at normal dosages, tranylcypromine proved no more effective than venlafaxine and mirtazapine in treatment-resistant depression, and was associated with worse side effects.
Contraindications
Therapeutic contraindicationContraindication
In medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action...
s of tranylcypromine include:
- CardiovascularCardiovascular diseaseHeart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
or cerebrovascular diseaseCerebrovascular diseaseCerebrovascular 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... - Drug abuseDrug abuseSubstance 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...
(due to the potential for interactionDrug interactionA 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...
s with certain agents, especially stimulantStimulantStimulants 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...
s) - Low body weightBody weightThe term body weight is 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 it is still measured in pounds or stones and pounds...
, anorexiaAnorexia (symptom)Anorexia is the decreased sensation of appetite...
, or eating disorderEating disorderEating disorders refer to a group of conditions defined by abnormal eating habits that may involve either insufficient or excessive food intake to the detriment of an individual's physical and mental health. Bulimia nervosa, anorexia nervosa, and binge eating disorder are the most common specific...
s of the sort - PheochromocytomaPheochromocytomaA pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
- Pre-existing and chronic headacheHeadacheA headache or cephalalgia 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...
s or migraineMigraineMigraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
s - PsychosisPsychosisPsychosis 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"...
such as schizophreniaSchizophreniaSchizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
or bipolar disorderBipolar disorderBipolar disorder or bipolar affective disorder, historically known as 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 with or without one or...
Dietary restrictions
Foods high in endogenousEndogenous
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...
monoamine precursors or exogenous
Exogenous
Exogenous refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system....
monoamine compound
Chemical compound
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...
s may cause adverse reactions. The most common example of this, is the hypertensive crisis caused by the ingestion of tyramine
Tyramine
Tyramine is a naturally occurring monoamine compound and trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent...
, which is found in foods like aged cheeses, cured meats, tofu
Tofu
is a food made by coagulating soy milk and then pressing the resulting curds into soft white blocks. It is 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...
and certain red wines. Some, such as yeast extract
Yeast extract
Yeast extract is the common name for various forms of processed yeast products made by extracting the cell contents ; they are used as food additives or flavourings, or as nutrients for bacterial culture media. They are often used to create savory flavors and umami taste sensations. Monosodium...
s, 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 effectAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s of tranylcypromine may include anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
or nervousness
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, irritability
Irritability
Irritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
, anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
and subsequent weight loss
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, mydriasis
Mydriasis
Mydriasis is a dilation of the pupil due to disease, trauma or the use of drugs. Normally, the pupil dilates in the dark and constricts in the light to respectively improve vividity at night and to protect the retina from sunlight damage during the day...
, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
or hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, hyperthermia
Hyperthermia
Hyperthermia is an elevated body temperature due to failed thermoregulation. Hyperthermia occurs when the body produces or absorbs more heat than it can dissipate...
, increased perspiration, muscle tremors, sexual dysfunction
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
consisting of erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
and/or anorgasmia
Anorgasmia
Anorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...
, and orthostatic
Orthostatic hypotension
Orthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...
or postural hypotension.
Tranylcypromine is typically considered to have fewer side effects than the hydrazine
Hydrazine
Hydrazine is an inorganic compound with the formula N2H4. It is a colourless flammable liquid with an ammonia-like odor. Hydrazine is highly toxic and dangerously unstable unless handled in solution. Approximately 260,000 tons are manufactured annually...
s, such as phenelzine
Phenelzine
Phenelzine is a non-selective and irreversible monoamine oxidase inhibitor of the hydrazine class which is used as an antidepressant and anxiolytic...
(Nardil).
At least one case of the abuse
Substance abuse
A substance-related disorder is an umbrella term used to describe several different conditions associated with several different substances .A substance related disorder is a condition in which an individual uses or abuses a...
of tranylcypromine has been noted. Sequelae included the periodic elimination of REM sleep and substantially elevated nocturnal muscle tone
Muscle tone
In physiology, medicine, and anatomy, muscle tone is the continuous and passive partial contraction of the muscles, or the muscle’s resistance to passive stretch during resting state. It helps maintain posture, and it declines during REM sleep.-Purpose:Unconscious nerve impulses maintain the...
. Attempts to discontinue the medication resulted in nightmares accompanied by prompt and grossly excessive nocturnal REM sleep, and narcolepsy
Narcolepsy
Narcolepsy is a chronic sleep disorder, or dyssomnia, characterized by excessive sleepiness and sleep attacks at inappropriate times, such as while at work. People with narcolepsy often experience disturbed nocturnal sleep and an abnormal daytime sleep pattern, which often is confused with insomnia...
.
Overdose
Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects. They may include exacerbated anxietyAnxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, muscle tremors, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
or hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, and hyperthermia
Hyperthermia
Hyperthermia is an elevated body temperature due to failed thermoregulation. Hyperthermia occurs when the body produces or absorbs more heat than it can dissipate...
, among others. Rare cases have been reported of hypertensive crisis, serotonin syndrome
Serotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
, myoclonus
Myoclonus
Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. Brief twitches are perfectly normal. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief...
, hyperpyrexia, psychosis
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"...
, and delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
, some of which progressed to coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
. Additionally, in sensitive individuals or at extreme dosages, hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
may lead to shock.
Pharmacology
Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase. Regarding the isoforms of monoamine oxidase, it shows slight preference for the MAOB isoenzyme over MAOA. In addition, tranylcypromine functions as a norepinephrineNorepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
releasing agent
Releasing agent
A releasing agent , or simply releaser, is a drug that induces the release of a neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs use neurotransmitter release to exert their psychological and...
(NDRA) with approximately 1/10 the potency
Potency (pharmacology)
In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...
of amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
.
As a result of these actions, tranylcypromine considerably boosts the concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
s and activity of the monoamine neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, along with paradoxical and varying effects on norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
and epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
. It increases the levels of the trace amine
Trace amine
Trace amines are endogenous compounds structurally related to classical biogenic amines, such as catecholamines, serotonin and histamine. Trace amines include p-tyramine, β-phenylethylamine, tryptamine, octopamine, and 3-iodothyronamine, and are found in the nervous systems of animals from insects...
s phenethylamine
Phenethylamine
Phenylethylamine or phenethylamine is a natural monoamine alkaloid, trace amine, and also the name of a class of chemicals with many members well known for psychoactive drug and stimulant effects. Studies suggest that phenylethylamine functions as a neuromodulator or neurotransmitter in the...
, tyramine
Tyramine
Tyramine is a naturally occurring monoamine compound and trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent...
, octopamine
Octopamine
Octopamine is an endogenous biogenic amine that is closely related to norepinephrine, and has effects on the adrenergic and dopaminergic systems. It is also found naturally in numerous plants, including bitter orange. Biosynthesis of the D--enantiomer of octopamine is by β-hydroxylation of...
, and tryptamine
Tryptamine
Tryptamine is a monoamine alkaloid found in plants, fungi, and animals. It is based around the indole ring structure, and is chemically related to the amino acid tryptophan, from which its name is derived...
as well. It is believed to be tranylcypromine's action on these neurochemical
Neurochemical
A neurochemical is an organic molecule, such as serotonin, dopamine, or nerve growth factor, that participates in neural activity. The science of neurochemistry studies the functions of neurochemicals.-Prominent neurochemicals:...
s that is responsible for its therapeutic efficacy
Efficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...
.
Tranylcypromine has also been shown to inhibit the histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
demethylase, BHC110/LSD1
LSD1
LSD1 is a gene which codes a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone 3, lysines 4 and 9 .-See also:* Histone methylation...
. 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.
Synthesis
Several methods of chemical synthesisChemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
for tranylcypromine are known.
Traditional:
- Styrene is reacted with ethyl diazoacetateEthyl diazoacetateEthyl diazoacetate is a diazo compound and a reagent in organic chemistry. It was discovered by Theodor Curtius in 1883. The compound can be prepared by reaction of the ethyl ester of glycine with sodium nitrite and sodium acetate in water....
to give ethyl 2-phenylcyclopropanecarboxylate. - Hydrolysis of ethyl 2-phenylcyclopropanecarboxylate in the presence of alkaliAlkaliIn chemistry, an alkali is a basic, ionic salt of an alkali metal or alkaline earth metal element. Some authors also define an alkali as a base that dissolves in water. A solution of a soluble base has a pH greater than 7. The adjective alkaline is commonly used in English as a synonym for base,...
forms 2-phenylcyclopropanecarboxylic acid. - 2-phenylcyclopropanecarboxylic acid is reacted with thionyl chlorideThionyl chlorideThionyl chloride is an inorganic compound with the formula SOCl2. It is a reactive chemical reagent used in chlorination reactions. It is a colorless, distillable liquid at room temperature and pressure that decomposes above 140 °C. Thionyl chloride is sometimes confused with sulfuryl...
(SOCl2) to form 2-phenylcyclopropanecarbonyl chloride. - 2-phenylcyclopropanecarbonyl chloride is reacted with sodium azideSodium azideSodium azide is the inorganic compound with the formula NaN3. This colourless azide salt is the gas-forming component in many car airbag systems. It is used for the preparation of other azide compounds. It is an ionic substance and is highly soluble in water. It is extremely...
(NaN3). - The resulting azideAzideAzide is the anion with the formula N3−. It is the conjugate base of hydrazoic acid. N3− is a linear anion that is isoelectronic with CO2 and N2O. Per valence bond theory, azide can be described by several resonance structures, an important one being N−=N+=N−...
of the above step is then the subject of a Curtius rearrangementCurtius rearrangementThe Curtius rearrangement , as first defined by Theodor Curtius, is a chemical reaction that involves the rearrangement of an acyl azide to an isocyanate. Several reviews have been published....
. - The resulting isocyanateIsocyanateIsocyanate is the functional group of elements –N=C=O , not to be confused with the cyanate functional group which is arranged as –O–C≡N or with isocyanide, R-N≡C. Any organic compound which contains an isocyanate group may also be referred to in brief as an isocyanate. An isocyanate may have more...
of the above step is hydrolyzed in a Schmidt reactionSchmidt reactionThe Schmidt reaction is an organic reaction involving alkyl migration over the carbon-nitrogen chemical bond in an azide with expulsion of nitrogen...
to realize 2-phenylcyclopropylamine as the product. - There are now four stereoisomers of the final compound:
- (1S,2R)-trans-2-phenylcyclopropylamine
- (1R,2S)-trans-2-phenylcyclopropylamine
- (1R,2R)-cis-2-phenylcyclopropylamine
- (1S,2S)-cis-2-phenylcyclopropylamine
- 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 acidTartaric acidTartaric acid is a white crystalline diprotic organic acid. It occurs naturally in many plants, particularly grapes, bananas, and tamarinds; is commonly combined with baking soda to function as a leavening agent in recipes, and is one of the main acids found in wine. It is added to other foods to...
, resulting in tranylcypromine.
Modern:
- Styrene is reacted with ethyl diazoacetateEthyl diazoacetateEthyl diazoacetate is a diazo compound and a reagent in organic chemistry. It was discovered by Theodor Curtius in 1883. The compound can be prepared by reaction of the ethyl ester of glycine with sodium nitrite and sodium acetate in water....
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 alkaliAlkaliIn chemistry, an alkali is a basic, ionic salt of an alkali metal or alkaline earth metal element. Some authors also define an alkali as a base that dissolves in water. A solution of a soluble base has a pH greater than 7. The adjective alkaline is commonly used in English as a synonym for base,...
forms 2-phenylcyclopropanecarboxylic acid. - 2-phenylcyclopropanecarboxylic acid is reacted with thionyl chlorideThionyl chlorideThionyl chloride is an inorganic compound with the formula SOCl2. It is a reactive chemical reagent used in chlorination reactions. It is a colorless, distillable liquid at room temperature and pressure that decomposes above 140 °C. Thionyl chloride is sometimes confused with sulfuryl...
(SOCl2) to form 2-phenylcyclopropanecarbonyl chloride. - 2-phenylcyclopropanecarbonyl chloride is reacted with sodium azideSodium azideSodium azide is the inorganic compound with the formula NaN3. This colourless azide salt is the gas-forming component in many car airbag systems. It is used for the preparation of other azide compounds. It is an ionic substance and is highly soluble in water. It is extremely...
(NaN3). - The resulting azideAzideAzide is the anion with the formula N3−. It is the conjugate base of hydrazoic acid. N3− is a linear anion that is isoelectronic with CO2 and N2O. Per valence bond theory, azide can be described by several resonance structures, an important one being N−=N+=N−...
of the above step is then the subject of a Curtius rearrangementCurtius rearrangementThe Curtius rearrangement , as first defined by Theodor Curtius, is a chemical reaction that involves the rearrangement of an acyl azide to an isocyanate. Several reviews have been published....
. - The resulting isocyanateIsocyanateIsocyanate is the functional group of elements –N=C=O , not to be confused with the cyanate functional group which is arranged as –O–C≡N or with isocyanide, R-N≡C. Any organic compound which contains an isocyanate group may also be referred to in brief as an isocyanate. An isocyanate may have more...
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 acidTartaric acidTartaric acid is a white crystalline diprotic organic acid. It occurs naturally in many plants, particularly grapes, bananas, and tamarinds; is commonly combined with baking soda to function as a leavening agent in recipes, and is one of the main acids found in wine. It is added to other foods to...
.