Iprindole
Encyclopedia
Iprindole formerly known as pramindole, is a tricyclic antidepressant
(TCA) used in Europe
for the treatment of depression. It was introduced by Wyeth
and has been used clinically since 1967. Notably, iprindole was the first second-generation antidepressant to be launched.
Iprindole is unique compared to most other TCAs in that it is a relatively weak inhibitor
of the reuptake
of serotonin
and norepinephrine
and instead acts predominantly as a antagonist
of 5-HT2 receptor
s, hence its classification as 'second-generation'. Additionally, side effect
s of iprindole are much less prominent relative to other TCAs and it is well-tolerated. However, iprindole's efficacy may not be as great as other TCAs, especially in regards to anxiety
relief.
in the United Kingdom
and Ireland
for the indication of major depressive disorder, and has also been sold as Galatur and Tertran by Wyeth as well.
It is unclear whether iprindole is available in any other countries.
level, iprindole differs from other TCAs in that it contains an indole
nucleus, similarly to the heterocyclic antipsychotic
oxypertine
, and has an eight-membered and saturated
third ring
.
(or inverse agonist
) at the following receptor
s:
And as an inhibitor
of the following transporters:
It has negligible affinity (>10,000 nM) for β-adrenergic and sigma receptor
s.
are either greatly reduced in comparison to imipramine
and most other TCAs or fully lacking with iprindole. However, it still has potent antihistamine
effects and therefore can produce sedation
, though this is diminished relative to imipramine as well, perhaps due to iprindole lacking significant alpha-blocking
properties.
and hepatotoxicity
and should not be taken by alcoholics or people with pre-existing liver disease
. If such symptoms are encountered iprindole should be discontinued immediately.
and/or N-dealkylation-mediated metabolism
of many substances including, but not limited to octopamine
, amphetamine
, methamphetamine
, fenfluramine
, phenelzine
, tranylcypromine
, trimipramine
, and fluoxetine
, likely via inactivating cytochrome P450 enzyme
s. It also inhibits its own degradation.
On account of these interactions, caution should be used when combining iprindole with other drugs. As an example, when administered with amphetamine or methamphetamine, iprindole increases their brain concentration
s and prolongs their half-live
s by 2- to 3-fold, strongly augmenting both their physiological effects and neurotoxicity
in the process.
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
(TCA) used in Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
for the treatment of depression. It was introduced by Wyeth
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...
and has been used clinically since 1967. Notably, iprindole was the first second-generation antidepressant to be launched.
Iprindole is unique compared to most other TCAs in that it is a relatively weak inhibitor
Reuptake inhibitor
A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
of the reuptake
Reuptake
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....
of 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 norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
and instead acts predominantly as a antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
of 5-HT2 receptor
5-HT2 receptor
The 5-HT2 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin . The 5-HT2 subfamily consists of three G protein-coupled receptors which are coupled to Gq/G11 and mediate excitatory neurotransmission, including 5-HT2A, 5-HT2B, and 5-HT2C...
s, hence its classification as 'second-generation'. Additionally, side effect
Side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.Occasionally, drugs are...
s of iprindole are much less prominent relative to other TCAs and it is well-tolerated. However, iprindole's efficacy may not be as great as other TCAs, especially in regards to 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,...
relief.
Availability
Iprindole is sold under the trade name Prondol by WyethWyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...
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...
and Ireland
Ireland
Ireland is an island to the northwest of continental Europe. It is the third-largest island in Europe and the twentieth-largest island on Earth...
for the indication of major depressive disorder, and has also been sold as Galatur and Tertran by Wyeth as well.
It is unclear whether iprindole is available in any other countries.
Chemistry
On a structuralChemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...
level, iprindole differs from other TCAs in that it contains an indole
Indole
Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an...
nucleus, similarly to the heterocyclic antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
oxypertine
Oxypertine
Oxypertine is an antipsychotic used in the treatment of schizophrenia. Chemically, it is an indole derivative similarly to molindone and a member of the phenylpiperazine class...
, and has an eight-membered and saturated
Saturation (chemistry)
In chemistry, saturation has six different meanings, all based on reaching a maximum capacity...
third ring
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
.
Pharmacology
Iprindole acts as an antagonistReceptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
(or inverse agonist
Inverse agonist
In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
) at the following receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s:
And as an inhibitor
Reuptake inhibitor
A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
of the following transporters:
- SERTSerotonin transporterThe serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
(Kd = 1,620 nM) - NETNorepinephrine transporterThe norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
(Kd = 1,262 nM) - DATDopamine transporterThe dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
(Kd = 6,530 nM)
It has negligible affinity (>10,000 nM) for β-adrenergic and sigma receptor
Sigma receptor
The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA 4503, ditolylguanidine, dimethyltryptamine and siramesine.- Classification :...
s.
Side effects
Anticholinergic side effects such as dry mouth and constipationConstipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
are either greatly reduced in comparison to imipramine
Imipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
and most other TCAs or fully lacking with iprindole. However, it still has potent antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
effects and therefore can produce sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
, though this is diminished relative to imipramine as well, perhaps due to iprindole lacking significant alpha-blocking
Alpha blocker
Alpha-1 blockers constitute a variety of drugs which block α1-adrenergic receptors in arteries and smooth muscles.-Pharmacology:...
properties.
Contraindications
Iprindole has been associated with jaundiceJaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
and hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
and should not be taken by alcoholics or people with pre-existing liver disease
Liver disease
Liver disease is a broad term describing any single number of diseases affecting the liver.-Diseases:* Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons , autoimmunity or hereditary conditions...
. If such symptoms are encountered iprindole should be discontinued immediately.
Interactions
Iprindole has been shown to be a potent inhibitor of the aromatic hydroxylationHydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...
and/or N-dealkylation-mediated metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of many substances including, but not limited to 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...
, 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,...
, methamphetamine
Methamphetamine
Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
, fenfluramine
Fenfluramine
Fenfluramine is a drug that was part of the Fen-Phen anti-obesity medication . Fenfluramine was introduced on the U.S. market in 1973. It is the racemic mixture of two enantiomers, dextrofenfluramine and levofenfluramine...
, phenelzine
Phenelzine
Phenelzine is a non-selective and irreversible monoamine oxidase inhibitor of the hydrazine class which is used as an antidepressant and anxiolytic...
, tranylcypromine
Tranylcypromine
Tranylcypromine is a drug of the substituted phenethylamine and amphetamine classes which acts as a monoamine oxidase inhibitor —it is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase...
, trimipramine
Trimipramine
Trimipramine is a tricyclic antidepressant . It has antidepressant, anxiolytic, antipsychotic, sedative, and analgesic effects.- Indications :...
, and fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
, likely via inactivating cytochrome P450 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...
s. It also inhibits its own degradation.
On account of these interactions, caution should be used when combining iprindole with other drugs. As an example, when administered with amphetamine or methamphetamine, iprindole increases their brain 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 prolongs their half-live
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
s by 2- to 3-fold, strongly augmenting both their physiological effects and neurotoxicity
Neurotoxicity
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
in the process.