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.
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 dopamine transporter is a membrane-spanning protein coded for in humans by the SLC6A3 gene, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.
Phenylpiracetam, also known as fonturacetam and sold under the brand names Phenotropil or Fenotropil and Carphedon, is a phenyl-substituted analog of the drug piracetam. It was developed in 1983 as a medication for Soviet cosmonauts to treat the prolonged stresses of working in space. Phenylpiracetam was created at the Russian Academy of Sciences Institute of Biomedical Problems in an effort led by psychopharmacologist Valentina Ivanovna Akhapkina. In Russia it is now available as a prescription drug. Research on animals has indicated that phenylpiracetam may have anti-amnesic, antidepressant, anticonvulsant, anxiolytic, and memory enhancement effects.
Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.
Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.
Mesocarb, sold under the brand name Sidnocarb or Sydnocarb and known by the developmental code name MLR-1017, is a psychostimulant medication which has been used in the treatment of psychiatric disorders and for a number of other indications in the Soviet Union and Russia. It is currently under development for the treatment of Parkinson's disease and sleep disorders. It is taken by mouth.
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon H. Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.
Difluoropine (O-620) is a stimulant drug synthesised from tropinone, which acts as a potent and selective dopamine reuptake inhibitor. Difluoropine is unique among the tropane-derived dopamine reuptake inhibitors in that the active stereoisomer is the (S) enantiomer rather than the (R) enantiomer, the opposite way round compared to natural cocaine. It is structurally related to benztropine and has similar anticholinergic and antihistamine effects in addition to its dopamine reuptake inhibitory action.
Bromantane, sold under the brand name Ladasten, is an atypical central nervous system (CNS) stimulant and anxiolytic drug of the adamantane family that is related to amantadine and memantine. Medically, it is approved in Russia for the treatment of neurasthenia. Although the effects of bromantane have been determined to be dependent on the dopaminergic and possibly serotonergic neurotransmitter systems, its exact mechanism of action is unknown, and is distinct in its properties relative to typical stimulants such as amphetamine. Bromantane has sometimes been described as an actoprotector.
A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.
A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective and robust DRAs are currently known. On the other hand, many releasing agents of both dopamine and norepinephrine and of serotonin, norepinephrine, and dopamine are known. Serotonin–dopamine releasing agents (SDRAs), for instance 5-chloro-αMT, are much more rare and are not selective for dopamine release but have also been developed. Examples of major NDRAs include the psychostimulants amphetamine and methamphetamine, while an example of an SNDRA is the entactogen methylenedioxymethamphetamine (MDMA). These drugs are frequently used for recreational purposes and encountered as drugs of abuse. Selective DRAs, as well as NDRAs, have medical applications in the treatment of attention deficit hyperactivity disorder (ADHD).
RTI(-4229)-113 is a stimulant drug which acts as a potent and fully selective dopamine reuptake inhibitor (DRI). It has been suggested as a possible substitute drug for the treatment of cocaine addiction. "RTI-113 has properties that make it an ideal medication for cocaine abusers, such as an equivalent efficacy, a higher potency, and a longer duration of action as compared to cocaine." Replacing the methyl ester in RTI-31 with a phenyl ester makes the resultant RTI-113 fully DAT specific. RTI-113 is a particularly relevant phenyltropane cocaine analog that has been tested on squirrel monkeys. RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by PET on awake rhesus monkeys. The efficacy of cocaine analogs to elicit self-administration is closely related to the rate at which they are administered. Slower onset of action analogs are less likely to function as positive reinforcers than analogues that have a faster rate of onset.
A eugeroic, or eugregoric, also known as a vigilance-promoting agent, is a type of drug that increases vigilance. The term has been used inconsistently and in multiple ways in the scientific literature, either to refer specifically to modafinil-type wakefulness-promoting agents or to refer to wakefulness-promoting agents generally. It was first introduced in the French literature in 1987 as a descriptor for modafinil-like wakefulness-promoting drugs and for purposes of distinguishing such drugs from psychostimulants. However, the term "eugeroic" has not been widely adopted in the literature, and instead the term "wakefulness-promoting agent" has been more widely used, both for modafinil-type drugs and other agents.
SoRI-20041 is an "antagonist-like" allosteric modulator of amphetamine-induced dopamine release. SoRI-20041 is believed to be the first example of a drug that separately modulates uptake versus release in the dopamine transporter ; it produces the same effects as SoRI-20040 and SoRI-9804 in uptake assays and binding assays, inhibiting the re-uptake of dopamine, but does not modulate d-amphetamine-induced DA release by inhibiting that as well, like 'agonists' of the series do.
JJC8-088 is a dopamine reuptake inhibitor (DRI) that was derived from the wakefulness-promoting agent modafinil.
CE-158 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It is often but not always referred to as the enantiopure enantiomer (S,S)-CE-158 instead.
JJC8-016 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It was an early lead in the development of novel modafinil analogues with improved properties for potential use in the treatment of psychostimulant use disorder (PSUD).
JJC8-091 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It is a lead compound for potential treatment of psychostimulant use disorder (PSUD) and is under development by Encepheal Therapeutics for use as a pharmaceutical drug.
JJC8-089 is a dopamine reuptake inhibitor (DRI) that was derived from modafinil and is related to JJC8-016, JJC8-088, and JJC8-091. Its affinity (Ki) for the dopamine transporter (DAT) is 37.8 nM, for the norepinephrine transporter (NET) is 11,820 nM, for the serotonin transporter (SERT) is 6,800 nM, and for the sigma σ1 receptor is 2.24 nM. It also has significant affinity for several dopamine receptors. JJC8-089 has substantially higher affinity for the DAT than modafinil. The drug shows pro-motivational effects in animals. It was first described in the scientific literature by 2016.
