Monoamine releasing agent

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Amphetamine, the prototypical monoamine releasing agent, which induces the release of dopamine and norepinephrine. Racemic amphetamine 2.svg
Amphetamine, the prototypical monoamine releasing agent, which induces the release of dopamine and norepinephrine.

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters. [2] [3] [4] [1] [5] The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; monoamine releasing agents can induce the release of one or more of these neurotransmitters. [2] [3] [4] [1] [5]

Contents

Monoamine releasing agents work by reversing the direction of the monoamine transporters (MATs), including the serotonin transporter (SERT), norepinephrine transporter (NET), and/or dopamine transporter (DAT), causing them to promote efflux of non-vesicular cytoplasmic monoamine neurotransmitter rather than reuptake of synaptic monoamine neurotransmitter. [5] [6] [1] [7] Many, but not all monoamine releasing agents, also reverse the direction of the vesicular monoamine transporter 2 (VMAT2), thereby additionally resulting in efflux of vesicular monoamine neurotransmitter into the cytoplasm. [5]

A variety of different classes of drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters. [2] [3] These include psychostimulants and appetite suppressants acting as dopamine and norepinephrine releasers like amphetamine, methamphetamine, and phentermine; sympathomimetic agents acting as norepinephrine releasers like ephedrine and pseudoephedrine; non-stimulant appetite suppressants acting as serotonin releasers like fenfluramine and chlorphentermine; and entactogens acting as releasers of serotonin and/or other monoamines like MDMA. [2] [3] Trace amines like phenethylamine and tryptamine, as well as the monoamine neurotransmitters themselves, are endogenous monoamine releasing agents. [2] [3] [4] It is thought that monoamine release by endogenous mediators may play some physiological regulatory role. [4]

MRAs must be distinguished from monoamine reuptake inhibitors (MRIs) and monoaminergic activity enhancers (MAEs), which similarly increase synaptic monoamine neurotransmitter levels and enhance monoaminergic signaling but work via distinct mechanisms. [5] [1] [8] [9]

Types and selectivity

MRAs can be classified by the monoamines they mainly release, although these drugs lie on a spectrum: [2] [3] [4] [5]

The differences in selectivity of MRAs 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.

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. [10] Several selective SDRAs, including tryptamine, (+)-α-ethyltryptamine (αET), 5-chloro-αMT, and 5-fluoro-αET, are known. [11] [12] 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. [11] [12]

Effects and uses

MRAs can produce varying effects depending on their selectivity for inducing the release of different monoamine neurotransmitters. [3]

Selective SRAs such as chlorphentermine have been described as dysphoric and lethargic. [13] [14] Less selective SRAs that also stimulate the release of dopamine, such as methylenedioxymethamphetamine (MDMA), are described as more pleasant, more reliably elevating mood and increasing energy and sociability. [15] 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) because they can produce much larger increases in serotonin levels in comparison. [16]

DRAs, usually non-selective for both norepinephrine and dopamine, have psychostimulant effects, causing an increase in energy, motivation, elevated mood, and euphoria. [17] Other variables can significantly affect the subjective effects, such as infusion rate (increasing positive effects of DRAs) and psychological expectancy effects. [18] 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. [19] They may also be performance-enhancing, [20] in contrast to reboxetine which is solely a norepinephrine reuptake inhibitor. [21] [22] 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.

Mechanism of action

MRAs cause the release of monoamine neurotransmitters by various complex mechanisms of action. 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). [23] 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, [23] [24] [25] [26] 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. [5] [6] [1] [7] Moreover, amphetamines continue to produce psychostimulant-like effects and induction of dopamine and norepinephrine release in TAAR1 knockout mice. [23] [27] [28] [29] [30] In fact, TAAR1 knockout mice are supersensitive to the effects of amphetamines and TAAR1 activation appears to inhibit the striatal dopaminergic effects of psychostimulants. [23] [28] [27] [29] [30] Additionally, many substrate-type MRAs that do not bind to and/or activate the (human) TAAR1 are known, including most cathinones, ephedrine, 4-methylamphetamine, and 4-methylaminorex derivatives, among others. [31] [32] [33] [34]

There is a constrained and relatively small molecular size requirement for compounds to act as monoamine releasing agents. [5] This is because they must be small enough to serve as substrates of the monoamine transporters and thereby be transported inside of monoaminergic neurons by these proteins, in turn allowing them to induce monoamine neurotransmitter release. [5] Compounds with chemical features extending beyond the size constraints for releasers will instead act as partial releasers, reuptake inhibitors, or be inactive. [5] Partial releasers show reduced maximal efficacy in releasing monoamine neurotransmitters compared to conventional full releasers. [5]

DAT "inverse agonists"

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. [7] [6] [5] [35] 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. [7] A variety of different pieces of evidence support this hypothesis and help to explain otherwise confusing findings. [7] 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. [7] 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 produces differing pharmacological effects from those of atypical DRIs. [6] [5] [35] [36]

Monoaminergic activity enhancers

Some MRAs, like the amphetamines amphetamine and methamphetamine, as well as trace amines like phenethylamine, tryptamine, and tyramine, are additionally monoaminergic activity enhancers (MAEs). [8] [9] [37] 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). [8] [9] [37] They are usually active as MAEs at much lower concentrations than those at which they induce monoamine release. [8] [9] [37] The MAE actions of MAEs may be mediated by TAAR1 agonism, which has likewise been implicated in monoamine-releasing actions. [38] [39] MAEs without concomitant potent monoamine-releasing actions, like selegiline (L-deprenyl), phenylpropylaminopentane (PPAP), and benzofuranylpropylaminopentane (BPAP), have been developed. [8] [9]

Endogenous MRAs

A number of endogenous compounds are known to act as MRAs. [4] [40] [41] [11] [5] These include the monoamine neurotransmitters dopamine (an NDRA), [40] norepinephrine (an NDRA), [40] and serotonin (an SRA) themselves, [40] as well as the trace amines phenethylamine (an NDRA), [5] [37] [42] [43] tryptamine (an SDRA or imbalanced SNDRA), [41] [11] and tyramine (an NDRA). [40] [4] Synthetic MRAs are substantially based on structural modification of these endogenous compounds, most prominently including the substituted phenethylamines and substituted tryptamines. [40] [2] [3] [41] [44] [45] [46]

Release of monoamine neurotransmitters by themselves, for instance in the cases of serotonin, norepinephrine, and dopamine, has been referred to as "self-release". [4] The physiological significance of the findings that monoamine neurotransmitters can act as releasing agents of themselves is unclear. [4] However, it could imply that efflux is a common neurotransmitter regulatory mechanism that can be induced by any transporter substrate. [4]

It is possible monoamine neurotransmitter self-release could be a protective mechanism. [4] It is notable in this regard that intracellular non-vesicular or cytoplasmic dopamine is toxic to neurons and that the vesicular monoamine transporter 2 (VMAT2) is neuroprotective by packaging this dopamine into synaptic vesicles. [47] [48] [49] Along similar lines, monoamine releasing agents induce the efflux of non-vesicular monoamine neurotransmitter and thereby move cytoplasmic neurotransmitter into the extracellular space. [5] However, many, though not all, monoamine releasing agents also act as VMAT2 inhibitors and reversers and hence concomitantly induce the release of vesicular monoamine neurotransmitter into the cytoplasm. [5]

Monoaminergic neurotoxicity

Some MRAs have been found to act as monoaminergic neurotoxins and hence to produce long-lasting damage to monoaminergic neurons. [50] [51] Examples include dopaminergic neurotoxicity with amphetamine and methamphetamine and serotonergic neurotoxicity with methylenedioxymethamphetamine (MDMA). [50] [51] Amphetamine may produce significant dopaminergic neurotoxicity even at therapeutic doses. [52] [53] [54] [55] [56] [57] However, clinical doses of amphetamine producing neurotoxicity is controversial and disputed. [58] [52] [54] In contrast to amphetamines, monoamine reuptake inhibitors like methylphenidate lack apparent neurotoxic effects. [52]

Analogues of MDMA with retained MRA activity but reduced or no serotonergic neurotoxicity, like 5,6-methylenedioxy-2-aminoindane (MDAI) and 5-iodo-2-aminoindane (5-IAI), have been developed. [59] [60] Certain drugs have been found to block the neurotoxicity of MRAs in animals. [51] For instance, the selective MAO-B inhibitor selegiline has been found to prevent the serotonergic neurotoxicity of MDMA in rodents. [51]

Activity profiles

Activity profiles of MRAs (EC50, nM) [2] [3]
Compound 5-HT Tooltip Serotonin NE Tooltip Norepinephrine DA Tooltip DopamineTypeClassRef
2-Aminoindane >1000086439NDRA Aminoindane [61]
2-APBT 8.921.638.6SNDRAAminopropylbenzothiophene [62]
2C-E >100000>100000>100000IA Phenethylamine [63]
2C-I >100000>100000>100000IAPhenethylamine [63]
3-APBT 21.913.421.7SNDRAAminopropylbenzothiophene [62]
3-Chloroamphetamine ND9.411.8NDAmphetamine [64] [4]
3-Chloromethcathinone 2111926SNDRACathinone [5]
3-Fluoroamphetamine 193716.124.2NDRA Amphetamine [65] [4]
3-Methoxyamphetamine ND58.0103NDAmphetamine [4]
3-Methoxy-4-hydroxymethamphetamine (HMMA)589625607–2884SNDRAAmphetamine [4] [66]
3-Methoxymethcathinone (3-MeOMC)306ND (68% at 10 μM)129SDRACathinone [67]
3-Methylamphetamine 21818.333.3NDRAAmphetamine [65] [64] [4]
3-Methylmethcathinone 2922770SNDRACathinone [5]
3,4-Dihydroxyamphetamine (HHA)ND333485NDAmphetamine [4]
3,4-Dihydroxymethamphetamine (HHMA)ND771729NDAmphetamine [4]
4-APBT 21.246.266.6SNDRAAminopropylbenzothiophene [62]
4-Chloroamphetamine ND23.568.5SNDRAAmphetamine [64] [4]
4-Fluoroamphetamine 730–93928.0–3751.5–200NDRAAmphetamine [65] [63] [64] [4]
4-Hydroxy-3-methoxyamphetamine (HMA)8976941450–3423NDAmphetamine [4] [66]
4-Methoxyamphetamine ND166867NDAmphetamine [4]
cis-4-Methylaminorex 53.24.81.7NDRA Aminorex [68]
4-Methylamphetamine 53.422.244.1SNDRAAmphetamine [65] [64] [4]
4-Methylphenethylamine NDND271NDPhenethylamine [5]
4-Methylthiomethamphetamine 21NDNDNDAmphetamine [69]
4,4'-Dimethylaminorex NDNDNDSNDRAAminorexND
  cis-4,4'-Dimethylaminorex17.7–18.511.8–26.98.6–10.9SNDRAAminorex [68] [70]
  trans-4,4'-Dimethylaminorex59.931.624.4SNDRAAminorex [70]
5-APB 192131SNDRAAmphetamine [71]
5-APBT 10.338.492.8SNDRAAminopropylbenzothiophene [62]
5-(2-Aminopropyl)indole (5-IT)28–104.813.3–7912.9–173SNDRAAmphetamine [12] [72]
  (R)-5-(2-Aminopropyl)indole177811062SNRAAmphetamine [12]
  (S)-5-(2-Aminopropyl)indoleNDNDNDSNDRAAmphetamineND
5-Chloro-αMT 16343454SDRA Tryptamine [11] [12]
5-Fluoro-αET 36.65334150SDRATryptamine [11]
5-Fluoro-αMT 1912632SNDRATryptamine [12]
5-MABB NDNDNDNDAmphetamine [73] [74]
  (R)-5-MABB49850IASRAAmphetamine [73] [74]
  (S)-5-MABB31158210SNDRAAmphetamine [73] [74]
5-MAPB (5-MBPB)642441SNDRAAmphetamine [71]
5-MeO-αMT 46089001500SNDRATryptamine [63]
5-MeO-AI 1348612646SNRAAminoindane [61]
5-MeO-DMT >100000>100000>100000IATryptamine [63]
6-APB 361410SNDRAAmphetamine [71]
6-APBT 10.713.67.2SNDRAAminopropylbenzothiophene [62]
6-(2-Aminopropyl)indole (6-IT)19.925.6164.0SNDRAAmphetamine [72]
6-Chloroamphetamine ND19.162.4NDAmphetamine [4]
6-Fluoroamphetamine ND24.138.1NDAmphetamine [4]
6-MABB (6-MBPB)NDNDNDNDAmphetamine [73] [74]
  (R)-6-MABB172227IASNRAAmphetamine [73] [74]
  (S)-6-MABB547741SNDRAAmphetamine [73] [74]
6-MAPB 331420SNDRAAmphetamine [71]
6-Methoxyamphetamine ND4731478NDAmphetamine [4]
6-Methylamphetamine ND37127NDAmphetamine [4]
7-APBT 36.928.516.8SNDRAAminopropylbenzothiophene [62]
α-Ethyltryptamine 23.2640232SDRATryptamine [11]
α-Methyltryptamine 21.7–6879–11278.6–180SNDRATryptamine [63] [11]
Amfepramone (diethylpropion) >10000>10000>10000PD Cathinone [75]
Aminorex 193–41415.1–26.49.1–49.4SNDRAAminorex [40] [68] [4]
Amphetamine NDNDNDNDRAAmphetamineND
   D-Amphetamine 698–17656.6–10.25.8–24.8NDRAAmphetamine [40] [76] [4]
   L-Amphetamine ND9.527.7NDRAAmphetamine [64] [4]
BDB 1805402,300NDRAAmphetamine [63]
Benzylpiperazine ≥605062–68175–600NDRA Arylpiperazine [63] [77] [3] [4]
BK-NM-AMT 41.3ND (55% at 10 μM)92.8SDRATryptamine [67] [78]
BK-5F-NM-AMT 190ND620NDTryptamine [79]
BK-5Cl-NM-AMT 200ND865NDTryptamine [79]
BK-5Br-NM-AMT 295ND2100NDTryptamine [79]
Bufotenin 30.5>10000>10000SRATryptamine [41]
Butylamphetamine NDNDIANDAmphetamine [5]
Cathinone 610023.683.1NDRACathinone [4] [67]
  D-CathinoneNDNDNDNRACathinoneND
  L-Cathinone236612.418.5NDRACathinone [80]
Chlorphentermine 30.9>100002650SRAAmphetamine [40]
DMPP 26561207SNRAArylpiperazine [69]
DMT 1144166>10000SRATryptamine [41]
Dopamine >10000 (RI)66.286.9NDRAPhenethylamine [40] [4]
DPT >100000>100000>100000IATryptamine [63] [41]
Ephedrine (racephedrine)NDNDNDNDRA Cathinol ND
   D-Ephedrine (ephedrine)>1000043.1–72.4236–1350NDRACathinol [40] [4]
  L-Ephedrine>100002182104NRACathinol [40] [80]
Epinephrine NDNDNDNDRAPhenethylamineND
Ethcathinone 211899.3>1000 (RI)NRACathinone [75] [4]
Ethylamphetamine NDND88.5NDAmphetamine [5]
Fenfluramine 79.3–108739>10000 (RI)SRAAmphetamine [40] [81] [82] [4]
   D-Fenfluramine 51.7302>10000SNRAAmphetamine [40] [81]
   L-Fenfluramine 147>10000>10000SRAAmphetamine [81] [83]
MBDB 5403300>100000SNRAAmphetamine [63]
mCPP 28–38.1≥140063000SRAArylpiperazine [63] [83] [84]
MDA 160–16247–108106–190SNDRAAmphetamine [82] [4] [71]
  (R)-MDA310290900SNDRAAmphetamine [82] [4]
  (S)-MDA10050.098.5SNDRAAmphetamine [82] [4]
MDAI 1141171334SNRAAminoindane [61]
MDEA 472608622SNDRAAmphetamine [69]
  (R)-MDEA52651507SNDRAAmphetamine [69]
  (S)-MDEA465RIRISRAAmphetamine [69]
MDMA 50–8554–11051–278SNDRAAmphetamine [40] [85] [72] [82] [4] [71]
   (R)-MDMA 3405603700SNDRAAmphetamine [82] [4]
   (S)-MDMA 74136142SNDRAAmphetamine [82] [4]
MDMAR NDNDNDSNDRAAminorexND
  cis-MDMAR43.914.810.2SNDRAAminorex [70]
  trans-MDMAR73.438.936.2SNDRAAminorex [70]
Mephedrone 118.3–12258–62.749.1–51SNDRACathinone [85] [76]
Methamnetamine 133410SNDRAAmphetamine [69]
Methamphetamine NDNDNDNDRAAmphetamineND
   D-Methamphetamine 736–1291.712.3–13.88.5–24.5NDRAAmphetamine [40] [85] [4]
   L-Methamphetamine 464028.5416NRAAmphetamine [40] [4]
Methcathinone ND22.449.9NDRACathinone [4]
  D-MethcathinoneNDNDNDNRACathinoneND
  L-Methcathinone177213.114.8NDRACathinone [80]
Methylone 234–242.1140–152.3117–133.0SNDRACathinone [85] [76]
MMAI 313101>10000SRAAminoindane [61]
Naphthylisopropylamine 3.411.112.6SNDRAAmphetamine [86] [4]
Norephedrine (phenylpropanolamine)NDNDNDNDRACathinolND
  D-Norephedrine>1000042.1302NDRACathinol [80]
  L-Norephedrine>100001371371NRACathinol [80]
Norepinephrine >10000164869NDRAPhenethylamine [40] [4]
Norfenfluramine 104168–1701900–1925SNRAAmphetamine [81] [82]
  (+)-Norfenfluramine59.372.7924SNRAAmphetamine [81]
  (–)-Norfenfluramine287474>10000SNRAAmphetamine [81]
Norpropylhexedrine NDNDNDNDRACyclohexethylamineND
Norpseudoephedrine NDNDNDNDRACathinolND
   D-Norpseudoephedrine (cathine)>1000015.068.3NDRACathinol [80]
   L-Norpseudoephedrine >1000030.1294NDRACathinol [80]
oMPP 17539.1296–542SNDRAArylpiperazine [87] [5]
PAL-738 236558SNDRA Phenylmorpholine [69]
PAL-874 >10000305688NDRAPhenylbutynamine [69]
Phenacylamine (β-ketophenethylamine)>10000ND208NDPhenethylamine [5] [67]
Phendimetrazine >100000>10000>10000PDPhenylmorpholine [88] [4]
Phenethylamine >1000010.939.5NDRAPhenethylamine [5] [64] [4]
Phenmetrazine 776550.4131NDRAPhenylmorpholine [88] [4]
Phentermine 351139.4262NDRAAmphetamine [40] [4]
Phenylalaninol NDNDNDNDAmphetamineND
  D-Phenylalaninol>100001061355NRAAmphetamine [87]
  L-PhenylalaninolNDNDNDNDAmphetamineND
Phenylisobutylamine NDND225NDAmphetamine [5]
Phenylpropylamine ND2221491NDRAPhenylpropylamine [64] [4]
pMPP 3200150011000SNRAArylpiperazine [63]
pNPP 43>10000>10000SRAArylpiperazine [69]
Propylamphetamine NDNDRI (1013)NDAmphetamine [5]
Propylhexedrine NDNDNDNDRACyclohexethylamineND
Pseudoephedrine (racemic pseudoephedrine)NDNDNDNDRACathinolND
   D-Pseudoephedrine >1000040929125NDRACathinol [80]
   L-Pseudoephedrine (pseudoephedrine)>100002241988NRACathinol [80]
Pseudophenmetrazine >10000514RINRAPhenylmorpholine [88]
Psilocin 561>10000>10000SRATryptamine [69] [41]
Serotonin 44.4>10000 (RI)≥1960SRATryptamine [40] [4]
TFMCPP 33>10000>10000SRAArylpiperazine [69]
TFMPP 121>10000>10000SRAArylpiperazine [77] [4]
Trimethoxyamphetamine 16000>100000>100000IAAmphetamine [63]
Tryptamine 32.6716164SDRATryptamine [41] [11]
Tyramine 277540.6119NDRAPhenethylamine [40] [4]
Notes: The smaller the value, the more strongly the substance releases the neurotransmitter.

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A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain.

A serotonin–dopamine releasing agent (SDRA) is a type of drug which induces the release of serotonin and dopamine in the body and/or brain.

<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">Substituted cathinone</span> Class of chemical compounds

Substituted cathinones, or simply cathinones, which include some stimulants and entactogens, are derivatives of cathinone. They feature a phenethylamine core with an alkyl group attached to the alpha carbon, and a ketone group attached to the beta carbon, along with additional substitutions. Cathinone occurs naturally in the plant khat whose leaves are chewed as a recreational drug.

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">Pseudophenmetrazine</span> Chemical compound

Pseudophenmetrazine is a psychostimulant compound of the morpholine class. It is the N-demethylated and cis-configured analogue of phendimetrazine as well as the cis-configured stereoisomer of phenmetrazine. In addition, along with phenmetrazine, it is believed to be one of the active metabolites of phendimetrazine, which itself is inactive and behaves merely as a prodrug. Relative to phenmetrazine, pseudophenmetrazine is of fairly low potency, acting as a modest releasing agent of norepinephrine (EC50 = 514 nM), while its (+)-enantiomer is a weak releaser of dopamine (EC50 = 1,457 nM) whereas its (−)-enantiomer is a weak reuptake inhibitor of dopamine (Ki = 2,691 nM); together as a racemic mixture with the two enantiomers combined, pseudophenmetrazine behaves overall more as a dopamine reuptake inhibitor (Ki = 2,630 nM), possibly due to the (+)-enantiomer blocking the uptake of the (−)-enantiomer into dopaminergic neurons and thus preventing it from inducing dopamine release. Neither enantiomer has any significant effect on serotonin reuptake or release (both Ki = >10,000 nM and EC50 = >10,000 nM, respectively).

<span class="mw-page-title-main">4-Hydroxy-3-methoxymethamphetamine</span> Chemical compound

4-Hydroxy-3-methoxymethamphetamine (HMMA) is an active metabolite of 3,4-methylenedioxymethamphetamine (MDMA). It is a slightly more potent stimulant than MDMA in rodents. The drug is substantially less potent than MDMA as a monoamine releasing agent in vitro. Nonetheless, HMMA has been found to induce the release of serotonin, norepinephrine, and dopamine with EC50Tooltip half-maximal effective concentration values of 589 nM, 625 nM, and 607–2884 nM, respectively, and hence acts as a lower-potency serotonin–norepinephrine–dopamine releasing agent (SNDRA). The predicted log P of HMMA is 1.2.

<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 drugs 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.

<span class="mw-page-title-main">Substituted β-hydroxyamphetamine</span> Class of compounds based upon the β-hydroxyamphetamine structure

Substituted β-hydroxyamphetamines, or simply β-hydroxyamphetamines, also known as substituted phenylisopropanolamines, substituted phenylpropanolamines, substituted norephedrines, or substituted cathinols, are derivatives of β-hydroxyamphetamine with one or more chemical substituents. They are substituted phenethylamines, phenylethanolamines (β-hydroxyphenethylamines), and amphetamines (α-methylphenethylamines), and are closely related to but distinct from the substituted cathinones (β-ketoamphetamines). Examples of β-hydroxyamphetamines include the β-hydroxyamphetamine stereoisomers phenylpropanolamine and cathine and the stereospecific N-methylated β-hydroxyamphetamine derivatives ephedrine and pseudoephedrine, among many others.

<span class="mw-page-title-main">BK-NM-AMT</span> Monoamine releaser and entactogen

BK-NM-AMT, or βk-NM-αMT, also known as β-keto-N-methyl-αMT or as α,N-dimethyl-β-ketotryptamine, is a serotonin–dopamine releasing agent (SDRA) and putative entactogen of the tryptamine and α-alkyltryptamine families. Along with certain other tryptamines, such as α-ethyltryptamine (αET), 5-chloro-αMT and 5-fluoro-αET, it is one of the few SDRAs known.

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