Monoamine releasing agent

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Amphetamine, the prototypical monoamine releasing agent, which acts on norepinephrine and dopamine. Racemic amphetamine 2.svg
Amphetamine, the prototypical monoamine releasing agent, which acts on norepinephrine and dopamine.

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.

Contents

Types of MRAs

MRAs can be classified by the monoamines they mainly release, although these drugs lie on a spectrum.

MRAs must be distinguished from monoamine reuptake inhibitors and monoaminergic activity enhancers, which work via distinct mechanisms.

Endogenous MRAs

A number of endogenous compounds are known to act as MRAs. [1] [2] [3] [4] These include the monoamine neurotransmitters dopamine (an NDRA), [1] norepinephrine (an NDRA), [1] and serotonin (an SRA) themselves, [1] as well as the trace amines phenethylamine (an NDRA), [4] [5] [6] [7] tryptamine (an SDRA or imbalanced SNDRA), [2] [3] and tyramine (an NDRA). [1] Synthetic MRAs are substantially based on structural modification of these endogenous compounds, most prominently including the substituted phenethylamines and substituted tryptamines. [1] [8] [9] [2] [10] [11] [12]

Mechanism of action

MRAs cause the release of monoamine neurotransmitters by various complex mechanism of actions. They may enter the presynaptic neuron primarily via plasma membrane transporters, such as the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT). Some, such as exogenous phenethylamine, amphetamine, and methamphetamine, can also diffuse directly across the cell membrane to varying degrees. Once inside the presynaptic neuron, they may inhibit the reuptake of monoamine neurotransmitters through vesicular monoamine transporter 2 (VMAT2) and release the neurotransmitters stores of synaptic vesicles into the cytoplasm by inducing reverse transport at VMAT2. MRAs can also bind to the intracellular receptor TAAR1 as agonists, which triggers a phosphorylation cascade via protein kinases that results in the phosphorylation of monoamine transporters located at the plasma membrane (i.e., the dopamine transporter, norepinephrine transporter, and serotonin transporter); upon phosphorylation, these transporters transport monoamines in reverse (i.e., they move monoamines from the neuronal cytoplasm into the synaptic cleft). [13] The combined effects of MRAs at VMAT2 and TAAR1 result in the release of neurotransmitters out of synaptic vesicles and the cell cytoplasm into the synaptic cleft where they bind to their associated presynaptic autoreceptors and postsynaptic receptors. Certain MRAs interact with other presynaptic intracellular receptors which promote monoamine neurotransmission as well (e.g., methamphetamine is also an agonist at σ1 receptor).

In spite of findings that TAAR1 activation by amphetamines can reverse the monoamine transporters and mediate monoamine release however, [13] [14] [15] [16] major literature reviews on monoamine releasing agents by experts like Richard B. Rothman and David J. Heal state that the nature of monoamine transport reversal is not well understood and/or do not mention TAAR1 activation. [17] [18] [19] [20] Moreover, amphetamines continue to produce psychostimulant-like effects and induction of dopamine and norepinephrine release in TAAR1 knockout mice. [13] [21] [22] [23] [24] In fact, TAAR1 knockout mice are supersensitive to the effects of amphetamines and TAAR1 activation appears to inhibit the striatal dopaminergic effects of psychostimulants. [13] [22] [21] [23] [24] Additionally, substrate-type MRAs that do not bind to the TAAR1, like 4-methylaminorex derivatives, are known. [25]

Dopamine reuptake inhibitors (DRIs) have been grouped into two types, typical or conventional DRIs like cocaine, WIN-35428 (β-CFT), and methylphenidate that produce potent psychostimulant, euphoric, and reinforcing effects, and atypical DRIs like vanoxerine (GBR-12909), modafinil, benztropine, and bupropion, which do not produce such effects or have greatly reduced such effects. [20] [18] [4] [26] It has been proposed that typical DRIs may not actually be acting primarily as DRIs but rather as dopamine releasing agents (DRAs) via mechanisms distinct from conventional substrate-type DRAs like amphetamines. [20] A variety of different pieces of evidence support this hypothesis and help to explain otherwise confusing findings. [20] Under this model, typical cocaine-like DRIs have been referred to with the new label of dopamine transporter (DAT) "inverse agonists" to distinguish them from conventional substrate-type DRAs. [20] An alternative theory is that typical DRIs and atypical DRIs stabilize the DAT in different conformations, with typical DRIs resulting in an outward-facing open conformation that results in differing pharmacological effects from those of atypical DRIs. [18] [4] [26] [27]

Some MRAs, like the amphetamines amphetamine and methamphetamine, as well as trace amines like phenethylamine, tryptamine, and tyramine, are additionally monoaminergic activity enhancers (MAEs). [28] [29] [5] That is, they induce the action potential-mediated release of monoamine neurotransmitters (in contrast to MRAs, which induced uncontrolled monoamine release independent of neuronal firing). [28] [29] [5] They are usually active as MAEs at much lower concentrations than those at which they induce monoamine release. [28] [29] [5] The MAE actions of MAEs may be mediated by TAAR1 agonism, which has likewise been implicated in monoamine-releasing actions. [30] [31] MAEs without concomitant potent monoamine-releasing actions, like selegiline (L-deprenyl), phenylpropylaminopentane (PPAP), and benzofuranylpropylaminopentane (BPAP), have been developed. [28] [29]

Effects and uses

MRAs can have a wide variety of effects depending upon their selectivity for inducing release of different monoamine neurotransmitters.

Selective SRAs such as fenfluramine and related compounds are described as dysphoric and lethargic in lower doses, and in higher doses some hallucinogenic effects have been reported. [32] [33] Less selective SRAs that also stimulate the release of dopamine, such as methylenedioxymethamphetamine (MDMA), are described as more pleasant, elevating mood and increasing energy and sociability. [34] SRAs have been used as appetite suppressants and as entactogens. They have also been proposed for use as more effective antidepressants and anxiolytics than selective serotonin reuptake inhibitors (SSRIs) owing to the fact that they can produce much larger increases in serotonin levels in comparison. [35]

DRAs, usually non-selective for both norepinephrine and dopamine, have psychostimulant effects, causing an increase in energy, motivation, elevated mood, and euphoria. [36] Other variables can significantly affect the subjective effects, such as infusion rate (increasing positive effects of DRAs) and psychological expectancy effects. [37] They are used in the treatment of attention deficit hyperactivity disorder (ADHD), as appetite suppressants, wakefulness-promoting agents, to improve motivation, and are drugs of recreational use and misuse.

Selective NRAs are minimally psychoactive, but as demonstrated by ephedrine, may be distinguished from placebo, and may trends towards liking. [38] They may also be performance-enhancing, [39] in contrast to reboxetine which is solely a norepinephrine reuptake inhibitor. [40] [41] In addition to their central effects, NRAs produce peripheral sympathomimetic effects like increased heart rate, blood pressure, and force of heart contractions. They are used as nasal decongestants and bronchodilators, but have also seen use as wakefulness-promoting agents, appetite suppressants, and antihypotensive agents. They have additionally seen use as performance-enhancing drugs, for instance in sports.

Selectivity

MRAs act to varying extents on serotonin, norepinephrine, and dopamine. Some induce the release of all three neurotransmitters to a similar degree, like methylenedioxymethamphetamine (MDMA), while others are more selective. As examples, amphetamine and methamphetamine are NDRAs but only very weak releasers of serotonin (~60- and 30-fold less than of dopamine, respectively) and MBDB is a fairly balanced SNRA but a weak releaser of dopamine (~6- and 10-fold lower of dopamine than of norepinephrine or serotonin, respectively). Even more selective include agents like fenfluramine, a selective SRA, and ephedrine, a selective NRA. The differences in selectivity of these agents is the result of different affinities as substrates for the monoamine transporters, and thus differing ability to gain access into monoaminergic neurons and induce monoamine neurotransmitter release via the TAAR1 and VMAT2 proteins.

As of present, no selective DRAs are known. This is because it has proven extremely difficult to separate DAT affinity from NET affinity and retain releasing efficacy at the same time. [42] Several selective SDRAs, including tryptamine, (+)-α-ethyltryptamine (αET), 5-chloro-αMT, and 5-fluoro-αET, are known. [3] [43] However, besides their serotonin release, these compounds additionally act as non-selective serotonin receptor agonists, including of the serotonin 5-HT2A receptor (with accompanying hallucinogenic effects), and some of them are known to act as monoamine oxidase inhibitors. [3] [43]

Activity profiles

Activity profiles of MRAs (EC50, nM) [8] [9]
Compound 5-HT Tooltip Serotonin NE Tooltip Norepinephrine DA Tooltip DopamineTypeClassRef
2C-E >100000>100000>100000IA Phenethylamine [44]
2C-I >100000>100000>100000IAPhenethylamine [44]
3-Chloromethcathinone NDND46.8NDCathinone [4]
3-Fluoroamphetamine 193716.124.2NDRA Amphetamine [45]
3-Methylamphetamine 21818.333.3NDRAAmphetamine [45]
4-Fluoroamphetamine 730–93928.0–3751.5–200NDRAAmphetamine [45] [44]
cis-4-Methylaminorex 53.24.81.7NDRA Aminorex [46]
4-Methylamphetamine 53.422.244.1SNDRAAmphetamine [45]
4-Methylphenethylamine NDND271NDPhenethylamine [4]
4-Methylthiomethamphetamine 21NDNDNDAmphetamine [47]
4,4'-Dimethylaminorex NDNDNDSNDRAAminorexND
   ''cis''-4,4'-Dimethylaminorex 17.7–18.511.8–26.98.6–10.9SNDRAAminorex [46] [48]
   ''trans''-4,4'-Dimethylaminorex 59.931.624.4SNDRAAminorex [48]
5-(2-Aminopropyl)indole 28–104.813.3–7912.9–173SNDRAAmphetamine [43] [49]
   (''R'')-5-(2-Aminopropyl)indole 177811062SNRAAmphetamine [43]
   (''S'')-5-(2-Aminopropyl)indole NDNDNDSNDRAAmphetamineND
5-Chloro-αMT 16343454SDRA Tryptamine [3] [43]
5-Fluoro-αET 36.65334150SDRATryptamine [3]
5-Fluoro-αMT 1912632SNDRATryptamine [43]
5-MeO-αMT 46089001500SNDRATryptamine [44]
5-MeO-DMT >100000>100000>100000IATryptamine [44]
6-(2-Aminopropyl)indole 19.925.6164.0SNDRAAmphetamine [49]
α-Ethyltryptamine 23.2640232SDRATryptamine [3]
α-Methyltryptamine 21.7–6879–11278.6–180SNDRATryptamine [44] [3]
Amfepramone (diethylpropion) >10000>10000>10000PD Cathinone [50]
Aminorex 193–41415.1–26.49.1–49.4SNDRAAminorex [1] [46]
Amphetamine NDNDNDNDRAAmphetamineND
   D-Amphetamine 698–17656.6–7.25.8–24.8NDRAAmphetamine [1] [51]
   L-Amphetamine NDNDNDNRAAmphetamineND
β-Ketophenethylamine NDND208NDPhenethylamine [4]
BDB 1805402,300NDRAAmphetamine [44]
Benzylpiperazine ≥605062–68175–600NDRA Arylpiperazine [44] [52] [9]
Bufotenin 30.5>10000>10000SRATryptamine [2]
Butylamphetamine NDNDIANDAmphetamine [4]
Cathinone NDNDNDNDRACathinoneND
   D-Cathinone NDNDNDNRACathinoneND
   L-Cathinone 236612.418.5NDRACathinone [53]
Chlorphentermine 30.9>100002650SRAAmphetamine [1]
DMPP 26561207SNRAArylpiperazine [47]
DMT 1144166>10000SRATryptamine [2]
Dopamine >1000066.286.9NDRAPhenethylamine [1]
DPT >100000>100000>100000IATryptamine [44] [2]
Ephedrine NDNDNDNDRA Cathinol ND
   D-Ephedrine >1000043.1–72.4236–1350NDRACathinol [1]
   L-Ephedrine >100002182104NRACathinol [1] [53]
Epinephrine NDNDNDNDRAPhenethylamineND
Ethcathinone 211899.3>1000NRACathinone [50]
Ethylamphetamine NDND296NDAmphetamine [4]
Fenfluramine 79.3–108739>10000SRAAmphetamine [1] [54] [55]
   D-Fenfluramine 51.7302>10000SNRAAmphetamine [1] [54]
   L-Fenfluramine 147>10000>10000SRAAmphetamine [54] [56]
MBDB 5403300>100000SNRAAmphetamine [44]
mCPP 28–38.1≥140063000SRAArylpiperazine [44] [56] [57]
MDA 160108190SNDRAAmphetamine [55]
   (''R'')-MDA 310290900SNDRAAmphetamine [55]
   (''S'')-MDA 1005098SNDRAAmphetamine [55]
MDEA 472608622SNDRAAmphetamine [47]
   (''R'')-MDEA 52651507SNDRAAmphetamine [47]
   (''S'')-MDEA 465RIRISRAAmphetamine [47]
MDMA 49.6–7254.1–11051.2–278SNDRAAmphetamine [1] [58] [49] [55]
  (''R'')-MDMA 3405603700SNDRAAmphetamine [55]
   (''S'')-MDMA 74136142SNDRAAmphetamine [55]
MDMAR NDNDNDSNDRAAminorexND
   ''cis''-MDMAR 43.914.810.2SNDRAAminorex [48]
   ''trans''-MDMAR 73.438.936.2SNDRAAminorex [48]
Mephedrone 118.3–12258–62.749.1–51SNDRACathinone [58] [51]
Methamnetamine 133410SNDRAAmphetamine [47]
Methamphetamine NDNDNDNDRAAmphetamineND
   D-Methamphetamine 736–1291.712.3–13.88.5–24.5NDRAAmphetamine [1] [58]
   L-Methamphetamine 464028.5416NRAAmphetamine [1]
Methcathinone NDNDNDNDRACathinoneND
   D-Methcathinone NDNDNDNRACathinoneND
   L-Methcathinone 177213.114.8NDRACathinone [53]
Methylone 234–242.1140–152.3117–133.0SNDRACathinone [58] [51]
Naphthylisopropylamine 3.411.112.6SNDRAAmphetamine [59]
Norephedrine NDNDNDNDRACathinolND
   D-Norephedrine >1000042.1302NDRACathinol [53]
   L-Norephedrine (phenylpropanolamine)>100001371371NRACathinol [53]
Norepinephrine >10000164869NDRAPhenethylamine [1]
Norfenfluramine 104168–1701900–1925SNRAAmphetamine [54] [55]
Norpropylhexedrine NDNDNDNDRACyclohexethylamineND
Norpseudoephedrine NDNDNDNDRACathinolND
   D-Norpseudoephedrine (cathine)>1000015.068.3NDRACathinol [53]
   L-Norpseudoephedrine >1000030.1294NDRACathinol [53]
oMPP 17539.1296–542SNDRAArylpiperazine [60] [4]
PAL-738 236558SNDRA Phenylmorpholine [47]
Phendimetrazine >100000>10000>10000PDPhenylmorpholine [61]
Phenethylamine NDND39.5NDRAPhenethylamine [4]
Phenmetrazine 776550.4131NDRAPhenylmorpholine [61]
Phentermine 351139.4262NDRAAmphetamine [1]
Phenylalaninol NDNDNDNDAmphetamineND
   D-Phenylalaninol >100001061355NRAAmphetamine [60]
   L-Phenylalaninol NDNDNDNDAmphetamineND
Phenylisobutylamine NDND225NDAmphetamine [4]
pMPP 3200150011000SNRAArylpiperazine [44]
pNPP 43>10000>10000SRAArylpiperazine [47]
Propylamphetamine NDNDRI (1013)NDAmphetamine [4]
Propylhexedrine NDNDNDNDRACyclohexethylamineND
Pseudoephedrine NDNDNDNDRACathinolND
   D-Pseudoephedrine >1000040929125NDRACathinol [53]
   L-Pseudoephedrine >100002241988NRACathinol [53]
Pseudophenmetrazine >10000514RINRAPhenylmorpholine [61]
Psilocin 561>10000>10000SRATryptamine [47] [2]
Serotonin 44.4>10000>10000SRATryptamine [1]
TFMCPP 33>10000>10000SRAArylpiperazine [47]
TFMPP 121ND>10000SRAArylpiperazine [52]
Trimethoxyamphetamine 16000>100000>100000IAAmphetamine [44]
Tryptamine 32.6716164SDRATryptamine [2] [3]
Tyramine 277540.6119NDRAPhenethylamine [1]
Notes: The smaller the value, the more strongly the substance releases the neurotransmitter.

See also

Related Research Articles

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<span class="mw-page-title-main">Tryptamine</span> Navbox for monoaminergic activity enhancers

Tryptamine is an indolamine metabolite of the essential amino acid, tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon. The structure of tryptamine is a shared feature of certain aminergic neuromodulators including melatonin, serotonin, bufotenin and psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin and others.

<span class="mw-page-title-main">Monoamine transporter</span> Proteins that function as integral plasma-membrane transporters

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.

<span class="mw-page-title-main">Fenfluramine</span> Medication used to treat seizures

Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome. It was formerly used as an appetite suppressant in the treatment of obesity, but was discontinued for this use due to cardiovascular toxicity before being repurposed for new indications. Fenfluramine was used for weight loss both alone under the brand name Pondimin and in combination with phentermine commonly known as fen-phen.

<span class="mw-page-title-main">Levmetamfetamine</span> Topical nasal decongestant

Levmetamfetamine, also known as l-desoxyephedrine or levomethamphetamine, and commonly sold under the brand name Vicks VapoInhaler among others, is an optical isomer of methamphetamine primarily used as a topical nasal decongestant. It is used to treat nasal congestion from allergies and the common cold. It was first used medically as decongestant beginning in 1958 and has been used for such purposes, primarily in the United States, since then.

<span class="mw-page-title-main">Trace amine</span> Amine receptors in the mammalian brain

Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.

<span class="mw-page-title-main">Etilamfetamine</span> Chemical compound

Etilamfetamine is a stimulant drug of the phenethylamine and amphetamine chemical classes. It was invented in the early 20th century and was subsequently used as an anorectic or appetite suppressant in the 1950s, but was not as commonly used as other amphetamines such as amphetamine, methamphetamine, and benzphetamine, and was largely discontinued once newer drugs such as phenmetrazine were introduced. It most likely acts primarily as a dopamine releasing agent. Its activity as a norepinephrine or serotonin releasing agent is not known.

<span class="mw-page-title-main">Naphthylaminopropane</span> Chemical compound

Naphthylaminopropane (PAL-287) is an experimental drug under investigation as of 2007 for the treatment of alcohol and stimulant addiction.

In pharmacology, an indirect agonist or indirect-acting agonist is a substance that enhances the release or action of an endogenous neurotransmitter but has no specific agonist activity at the neurotransmitter receptor itself. Indirect agonists work through varying mechanisms to achieve their effects, including transporter blockade, induction of transmitter release, and inhibition of transmitter breakdown.

<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

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.

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons.

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).

<span class="mw-page-title-main">3-Fluoroamphetamine</span> Stimulant drug that acts as an amphetamine

3-Fluoroamphetamine is a stimulant drug from the amphetamine family which acts as a monoamine releaser with similar potency to methamphetamine but more selectivity for dopamine and norepinephrine release over serotonin. It is self-administered by mice to a similar extent to related drugs such as 4-fluoroamphetamine and 3-methylamphetamine.

<span class="mw-page-title-main">Serotonin–dopamine reuptake inhibitor</span> Class of drug

A serotonin–dopamine reuptake inhibitor (SDRI) is a type of drug which acts as a reuptake inhibitor of the monoamine neurotransmitters serotonin and dopamine by blocking the actions of the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of serotonin and dopamine, and, therefore, an increase in serotonergic and dopaminergic neurotransmission.

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.

<span class="mw-page-title-main">Methamnetamine</span> Chemical compound

Methamnetamine is a triple monoamine releasing agent and N-methyl analog of the non-neurotoxic experimental drug naphthylaminopropane and the naphthalene analog of methamphetamine. It has been sold online as a designer drug.

<span class="mw-page-title-main">Substituted phenylmorpholine</span> Class of chemical compounds

Substituted phenylmorpholines, or substituted phenmetrazines alternatively, are chemical derivatives of phenylmorpholine or of the psychostimulant drug phenmetrazine. Most such compounds act as releasers of monoamine neurotransmitters, and have stimulant effects. Some also act as agonists at serotonin receptors, and compounds with an N-propyl substitution act as dopamine receptor agonists. A number of derivatives from this class have been investigated for medical applications, such as for use as anorectics or medications for the treatment of ADHD. Some compounds have also become subject to illicit use as designer drugs.

A release modulator, or neurotransmitter release modulator, is a type of drug that modulates the release of one or more neurotransmitters. Examples of release modulators include monoamine releasing agents such as the substituted amphetamines and release inhibitors such as botulinum toxin A.

<i>ortho</i>-Methylphenylpiperazine Chemical compound

ortho-Methylphenylpiperazine (also known as oMPP, oMePP, 1-(2-methylphenyl)piperazine, 2-MPP, and 2-MePP) is a psychoactive designer drug of the phenylpiperazine group. It acts as a serotonin–norepinephrine–dopamine releasing agent (SNDRA), with EC50 values for induction of monoamine release of 175 nM for serotonin, 39.1 nM for norepinephrine, and 296–542 nM for dopamine. As such, it has about 4.5-fold preference for induction of norepinephrine release over serotonin, and about 7.6- to 13.9-fold preference for induction of norepinephrine release over dopamine.

<span class="mw-page-title-main">Monoaminergic activity enhancer</span> Class of compounds in the nervous system

Monoaminergic activity enhancers (MAE), also known as catecholaminergic/serotonergic activity enhancers (CAE/SAE), are a class of compounds that enhance the action potential-evoked release of monoamine neurotransmitters in the nervous system. MAEs are distinct from monoamine releasing agents (MRAs) like amphetamine and fenfluramine in that they do not induce the release of monoamines from synaptic vesicles but rather potentiate only nerve impulse propagation-mediated monoamine release. That is, MAEs increase the amounts of monoamine neurotransmitters released by neurons per electrical impulse.

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