Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.
Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, obsessive–compulsive disorder (OCD), social phobia, attention-deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs), which act upon single neurotransmitters.
Isocarboxazid is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class used as an antidepressant. Along with phenelzine and tranylcypromine, it is one of only three classical MAOIs still available for clinical use in the treatment of psychiatric disorders in the United States, though it is not as commonly employed in comparison to the others.
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Iprindole, sold under the brand names Prondol, Galatur, and Tertran, is an atypical tricyclic antidepressant (TCA) that has been used in the United Kingdom and Ireland for the treatment of depression but appears to no longer be marketed. It was developed by Wyeth and was marketed in 1967. The drug has been described by some as the first "second-generation" antidepressant to be introduced. However, it was very little-used compared to other TCAs, with the number of prescriptions dispensed only in the thousands.
A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.
Indatraline hydrochloride is an antidepressive agent and non-selective monoamine transporter inhibitor that blocks the reuptake of dopamine, norepinephrine, and serotonin with similar efficacy to cocaine. This compound may be used to treat cocaine addictions as its effects have a slower onset and a longer duration than those of cocaine. Lu 19-005 has been shown to block the action of methamphetamine and MDMA in laboratory experiments.
The serotonin 1A receptor is a subtype of serotonin receptors, or 5-HT receptors, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarization and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.
Nisoxetine, originally synthesized in the Lilly research laboratories during the early 1970s, is a potent and selective inhibitor for the reuptake of norepinephrine (noradrenaline) into synapses. It currently has no clinical applications in humans, although it was originally researched as an antidepressant. Nisoxetine is now widely used in scientific research as a standard selective norepinephrine reuptake inhibitor. It has been used to research obesity and energy balance, and exerts some local analgesia effects.
Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.
LR-5182 is a stimulant drug which acts as a norepinephrine–dopamine reuptake inhibitor, structurally related to the better known drug fencamfamine. It was developed by the pharmaceutical company Eli Lilly in the 1970s, and researched for potential use as an antidepressant, although never marketed. LR-5182 has two stereoisomers, both of which are active, although one isomer blocks reuptake of only dopamine and noradrenaline, while the other blocks reuptake of serotonin as well.
Oxaprotiline, also known as hydroxymaprotiline, is a norepinephrine reuptake inhibitor belonging to the tetracyclic antidepressant (TeCA) family and is related to maprotiline. Though investigated as an antidepressant, it was never marketed.
Tropoxane (O-1072) is an aryloxytropane derivative drug developed by Organix Inc., which acts as a stimulant and potent dopamine and serotonin reuptake inhibitor. It is an analogue of dichloropane where the amine nitrogen has been replaced by an oxygen ether link, demonstrating that the amine nitrogen is not required for DAT binding and reuptake inhibition.
Bifemelane (INN) (Alnert, Celeport), or bifemelane hydrochloride (JAN), also known as 4-(O-benzylphenoxy)-N-methylbutylamine, is an antidepressant and cerebral activator that is widely used in the treatment of cerebral infarction patients with depressive symptoms in Japan, and in the treatment of senile dementia as well. It also appears to be useful in the treatment of glaucoma. Bifemelane acts as a monoamine oxidase inhibitor (MAOI) of both isoenzymes, with competitive (reversible) inhibition of MAO-A (Ki = 4.20 μM) (making it a reversible inhibitor of monoamine oxidase A (RIMA)) and non-competitive (irreversible) inhibition of MAO-B (Ki = 46.0 μM), and also acts (weakly) as a norepinephrine reuptake inhibitor. The drug has nootropic, neuroprotective, and antidepressant-like effects in animal models, and appears to enhance the cholinergic system in the brain.
Tametraline (CP-24,441) is the parent of a series of chemical compounds investigated at Pfizer that eventually led to the development of sertraline (CP-51,974-1).
Pridefine (AHR-1,118) is a drug which was investigated as an antidepressant in the late 1970s and early 1980s, but was never marketed. It acts as a balanced reuptake inhibitor of serotonin, dopamine, and norepinephrine, and also has some weak releasing activity.
Amedalin (UK-3540-1) is an antidepressant which was synthesized in the early 1970s, but was never marketed. It is a selective norepinephrine reuptake inhibitor, with no significant effects on the reuptake of serotonin and dopamine, and no antihistamine or anticholinergic properties.
Daledalin (UK-3557-15) is an antidepressant which was synthesized and trialed for depression in the early 1970s, but was never marketed. It is a selective norepinephrine reuptake inhibitor, with no significant effects on the reuptake of serotonin and dopamine, and no antihistamine or anticholinergic properties.
A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.
Selective serotonin reuptake inhibitors, or serotonin-specific re-uptake inhibitor (SSRIs), are a class of chemical compounds that have contributed to the major advances as antidepressants where they have revolutionised the treatment of depression and other psychiatric disorders. The SSRIs are therapeutically useful in the treatment of panic disorder (PD), posttraumatic stress disorder (PTSD), social anxiety disorder, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD), and anorexia. There is also clinical evidence of SSRIs efficiency in the treatment of the negative symptoms of schizophrenia and their ability to prevent cardiovascular diseases.
