A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.
The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membranes of synaptic vesicles of presynaptic neurons. It transports monoamine neurotransmitters – such as dopamine, serotonin, norepinephrine, epinephrine, and histamine – into the vesicles, which release the neurotransmitters into synapses, as chemical messages to postsynaptic neurons. VMATs utilize a proton gradient generated by V-ATPases in vesicle membranes to power monoamine import.
The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.
Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second messenger signaling cascade that induces a broad, long-lasting signal. This modulation can last for hundreds of milliseconds to several minutes. Some of the effects of neuromodulators include: altering intrinsic firing activity, increasing or decreasing voltage-dependent currents, altering synaptic efficacy, increasing bursting activity and reconfigurating synaptic connectivity.
Vanoxerine is a piperazine derivative which is a potent and selective dopamine reuptake inhibitor (DRI). Vanoxerine binds to the target site on the dopamine transporter (DAT) ~ 50 times more strongly than cocaine, but simultaneously inhibits the release of dopamine. This combined effect only slightly elevates dopamine levels, giving vanoxerine only mild stimulant effects. Vanoxerine has also been observed to be a potent blocker of the IKr (hERG) channel. Vanoxerine also binds with nanomolar affinity to the serotonin transporter.
2β-Propanoyl-3β-(2-naphthyl)-tropane or WF-23 is a cocaine analogue. It is several hundred times more potent than cocaine at being a serotonin-norepinephrine-dopamine reuptake inhibitor.
Dimethocaine, also known as DMC or larocaine, is a compound with a stimulatory effect. This effect resembles that of cocaine, although dimethocaine appears to be less potent. Just like cocaine, dimethocaine is addictive due to its stimulation of the reward pathway in the brain. However, dimethocaine is a legal cocaine replacement in some countries and is even listed by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) under the category “synthetic cocaine derivatives”. The structure of dimethocaine, being a 4-aminobenzoic acid ester, resembles that of procaine. It is found as a white powder at room temperature.
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.
Minaprine is a monoamine oxidase inhibitor antidepressant drug that was used in France for the treatment of depression until it was withdrawn from the market in 1996 because it caused convulsions.
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.
Amperozide is an atypical antipsychotic of the diphenylbutylpiperazine class which acts as an antagonist at the 5-HT2A receptor. It does not block dopamine receptors as with most antipsychotic drugs, but does inhibit dopamine release, and alters the firing pattern of dopaminergic neurons. It was investigated for the treatment of schizophrenia in humans, but never adopted clinically. Its main use is instead in veterinary medicine, primarily in intensively farmed pigs, for decreasing aggression and stress and thereby increasing feeding and productivity.
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.
Amfonelic acid is a research chemical and dopaminergic stimulant with antibiotic properties. Although limited clinical trials have been conducted, it's primarily used in scientific research.
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).
A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective DRAs are currently known. Many releasing agents of both dopamine and norepinephrine and of serotonin, norepinephrine, and dopamine are known, however. Serotonin–dopamine releasing agents are much rarer and are not selective for monoamine release. Examples of NDRAs include amphetamine and methamphetamine, and an example of an SNDRA is MDMA. The most selective dopamine releaser is 4-methylaminorex, but it also has considerable activity as a norepinephrine releaser. These drugs are frequently used for recreational purposes and encountered as drugs of abuse.
The plasma membrane monoamine transporter (PMAT) is a low-affinity monoamine transporter protein which in humans is encoded by the SLC29A4 gene. It is known alternatively as the human equilibrative nucleoside transporter-4 (hENT4). It was discovered in 2004 and has been identified as a potential alternate target for treating various conditions.
JNJ-7925476 is a triple reuptake inhibitor antidepressant discovered by Johnson & Johnson, but never marketed.
EXP-561 is an investigational drug that acts as an inhibitor of the reuptake of serotonin, dopamine, and norepinephrine. It was developed in the 1960s by Du Pont and was suggested as a potential antidepressant but failed in trials and was never marketed.
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.
