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Monoamine releasing agent

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"Releasing agent" redirects here. For mold release agents, see Release agent.
Amphetamine, the prototypical monoamine releasing agent, which induces the release of dopamine and norepinephrine.[1]

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; MRAs can induce the release of one or more of these neurotransmitters.[2][3][4][1][5]

MRAs 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 MRAs, 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 MRAs.[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

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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

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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

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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 some findings that TAAR1 activation by amphetamines can reverse the monoamine transporters and mediate monoamine release however,[23][24][25][26] major literature reviews on MRAs by recognized experts like on these agents 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 induce dopamine and norepinephrine release in in-vitro systems lacking the TAAR1, like HEK293 cells,[27] and produce monoamine release and psychostimulant-like effects in TAAR1 knockout mice.[23][28][29][30][31] In fact, TAAR1 knockout mice are supersensitive to the effects of amphetamines, and TAAR1 activation appears to inhibit the striatal dopaminergic actions of psychostimulants.[23][29][28][30][31] Additionally, numerous substrate-type MRAs that do not bind to and/or activate the (human) TAAR1 are known, including most cathinones, ephedrine, 4-methylamphetamine (4-MA), para-methoxyamphetamine (PMA), 4-methylthioamphetamine (4-MTA), MBDB, MDEA, 5-APDB, 5-MAPDB, meta-chlorophenylpiperazine (mCPP), TFMPP, 4-methylaminorex derivatives, and methylhexanamine, among others.[32][33][34][35] In addition, amphetamine and methamphetamine themselves only activate the human TAAR1 at micromolar concentrations and with potency an order of magnitude lower than phenethylamine.[34] However, there is indication that TAAR1, although non-essential for induction of monoamine release, might augment the releasing potency of amphetamines as dopamine releasing agents, at least in vitro.[26]

Generic pharmacophore for MRAs.[5] Substitutions at the nitrogen, α-carbon, or phenyl ring extending beyond the red circle will result in partial releasers, transporter blockers, or be inactive.[5]

There is a constrained and relatively small molecular size requirement for compounds to act as MRAs.[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]

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DAT "inverse agonists"

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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][36] 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][36][37]

Monoaminergic activity enhancers

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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][38] That is, they induce the action potential-mediated release of monoamine neurotransmitters (in contrast to MRAs, which induce uncontrolled monoamine release independent of neuronal firing).[8][9][38] They are usually active as MAEs at much lower concentrations than those at which they induce monoamine release.[8][9][38] The MAE actions of MAEs may be mediated by TAAR1 agonism, which has likewise been implicated in monoamine-releasing actions.[39][40] MAEs without concomitant potent monoamine-releasing actions, like selegiline (L-deprenyl), phenylpropylaminopentane (PPAP), and benzofuranylpropylaminopentane (BPAP), have been developed.[8][9]

Endogenous MRAs

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A number of endogenous compounds are known to act as MRAs.[4][41][42][11][5] These include the monoamine neurotransmitters dopamine (an NDRA),[41] norepinephrine (an NDRA),[41] and serotonin (an SRA) themselves,[41] as well as the trace amines phenethylamine (an NDRA),[5][38][43][44] tryptamine (an SDRA or imbalanced SNDRA),[42][11] and tyramine (an NDRA).[41][4] Synthetic MRAs are substantially based on structural modification of these endogenous compounds, most prominently including the substituted phenethylamines and substituted tryptamines.[41][2][3][42][45][46][47]

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 that monoamine neurotransmitter self-release could be a protective mechanism.[4][48] 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.[49][50][51][48] Along similar lines, MRAs induce the efflux of non-vesicular monoamine neurotransmitter and thereby move cytoplasmic neurotransmitter into the extracellular space.[5] On the other hand, many MRAs but not all also act as VMAT2 inhibitors and reversers, and hence concomitantly induce the release of vesicular monoamine neurotransmitters like dopamine into the cytoplasm.[5] Induction of VMAT2 efflux by MRAs appears to be related to their monoaminergic neurotoxicity.[52][53][54]

Monoaminergic neurotoxicity

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Main article: Monoaminergic neurotoxin

Some MRAs have been found to act as monoaminergic neurotoxins and hence to produce long-lasting damage to monoaminergic neurons.[55][56] Examples include dopaminergic neurotoxicity with amphetamine and methamphetamine and serotonergic neurotoxicity with methylenedioxymethamphetamine (MDMA).[55][56] Amphetamine may produce significant dopaminergic neurotoxicity even at therapeutic doses.[57][58][59][60][61][62] However, clinical doses of amphetamine producing neurotoxicity is controversial and disputed.[63][57][59] In contrast to amphetamines, monoamine reuptake inhibitors like methylphenidate lack apparent neurotoxic effects.[57]

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.[64][65] Certain drugs have been found to block the neurotoxicity of MRAs in animals.[56] For instance, the selective MAO-B inhibitor selegiline has been found to prevent the serotonergic neurotoxicity of MDMA in rodents.[56]

Chemical families

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MRAs are usually arylalkylamines. A number of different structural families of compounds have been found to act as MRAs. The possible structural forms of MRAs are limited by a small molecular size requirement for activity.[5] Molecules that are too large become monoamine reuptake inhibitors as they can no longer be transported into neurons by the monoamine transporters and induce monoamine release intracellularly.[5]

Phenethylamine-like

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Amine fused into ring

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Alkyl chain fused into ring

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Tryptamine-like

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Ring-less (alkylamines)

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Chemical family structure examples of monoamine releasing agents

Activity profiles

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See also: Monoamine reuptake inhibitor § Binding profiles

The activities of many MRAs in terms of their potencies, efficacies, and selectivities for monoamine release induction in vitro have been characterized in numerous studies in the scientific literature.[2][103][3][5][104] These studies have been especially conducted by the research lab led by Richard B. Rothman and Michael H. Baumann at the National Institute on Drug Abuse (NIDA).[2][103][3][104] These researchers developed an assay measuring monoamine release from rat brain synaptosomes in 1999 that has subsequently been widely employed.[104][103][41][105][106] The data with this procedure from many relevant studies are provided in the table below.[2][3] The Rothman and Baumann lab refers to these data as the "Phenyl Amine Library", "Phenethylamine Library", "Phenylethylamine Library", or "PAL" library, a large library of values of phenethylamine analogs at the monoamine transporters, and has designated PAL-# code names for the drugs included in it.[107][5][104]

Another method of measuring monoamine release involves the use of human HEK293 cells transfected with and expressing monoamine transporters.[108][109][64][110][67] However, MRAs show differing and much lower potencies in this system compared to rat brain synaptosomes, and it is much less frequently employed.[108][109][64][110][67] The reasons for these differences are not entirely clear, but may be related to species differences, differences in release assay methods, and/or absence of important neuronal membrane proteins in non-neuronal HEK293 cells.[67][26] One possible difference in terms of the use of non-neuronal cells may be that TAAR1 is present in rat brain synaptosomes but is absent in HEK293 cells.[26][27] The monoamine-releasing activities of phenethylamine are abolished in the brain synaptosomes of TAAR1 knockout mice.[111] Conversely however, while TAAR1 may also be involved in the releasing effects of amphetamines, the TAAR1 is not essential for monoamine release induced by amphetamines and other MRAs.[27][23][24][25][26][34]

Activity profiles of monoamine releasing agents in rat brain synaptosomes (EC50Tooltip half-maximal effective concentration, nM)[2][3][4]
Compound PAL # 5-HTTooltip Serotonin NETooltip Norepinephrine DATooltip Dopamine Type Class Ref
1-Methyl-T PAL-637 53.1 >10000 >10000 SRA Tryptamine [11]
1-Phenylpiperazine (PP) ND 880 186 2530 SNRA Phenylpiperazine [86]
2-Aminoindane (2-AI, AI) ND >10000 86 439 NDRA Aminoindane [87]
2-APBT ND 8.9 21.6 38.6 SNDRA APBT [74]
2-BMC ND 2837 156 650 NDRA Cathinone [112]
2-CA ND ND 19.1 62.4 ND Amphetamine [4]
2-CMC ND 2815 93 179 NDRA Cathinone [112]
2-FA ND ND 24.1 38.1 ND Amphetamine [4]
2-FMA ND ~15000 <100 ~90 NDRA Amphetamine [113][114]
2-FMC ND >10000 ND
(85% at 10 μM)		 48.7 NDRA Cathinone [93]
2-FPM ND 4808 28 112 NDRA Phenylmorpholine [115]
2-MA ND ND 37 127 ND Amphetamine [4]
2-MeO-A ND ND 473 1478 ND Amphetamine [4]
2-MeO-MC ND 7220 339 920 NDRA Cathinone [112]
2-MMC ND 347–490 53 81–97.9 SNDRA Cathinone [93][112]
2-MPM ND 1758 102 374 NDRA Phenylmorpholine [116]
2-Phenylmorpholine PAL-632 20260
(31% at 10 μM)		 79
(96% at 10 μM)		 86
(98% at 10 μM)		 NDRA Phenylmorpholine [117]
2-TFMeO-MC ND >10000 ND
(33% at 10 μM)		 >10000 IA Cathinone [93]
2-TFMMC (2-TFMAP) ND 8400–>10000 2200
(69% at 10 μM)		 8000–>10000 SNDRA Cathinone [118][93][119][112]
2C-C ND >100000 >100000 100000 IA Phenethylamine [66][120]
2C-D ND IA IA IA IA Phenethylamine [120]
2C-E ND >100000 >100000 >100000 IA Phenethylamine [66][120]
2C-I ND >100000 >100000 >100000 IA Phenethylamine [66][120]
2C-T-2 ND IA IA IA IA Phenethylamine [120]
3-APBT ND 21.9 13.4 21.7 SNDRA APBT [74]
3-BCPC PAL-586 621 ND IA (RI) ND Cathinone [107]
3-BMC ND 136–137 25 21–28.0 SNDRA Cathinone [93][121][112]
3-CA PAL-304 120 9.4 11.8 SNDRA Amphetamine [81][4][107][107][122]
3-CC ND 567 105 64 SNDRA Cathinone [123][121]
3-CCPC (RTI-6037-39) PAL-433 1328 ND IA (RI) ND Cathinone [107][124]
  (–)-3-CCPC PAL-1122 562 ND IA (RI) ND Cathinone [107]
  (+)-3-CCPC PAL-1123 733 ND IA (RI) ND Cathinone [107]
3-CEC PAL-361 IA ND IA ND Cathinone [107]
3-Cl-4-Me-CPC PAL-820 181 ND IA (RI) ND Cathinone [107]
3′-Cl-5-Me-PM PAL-738 23 65 58 SNDRA Phenylmorpholine [78][125]
3-CMC (clophedrone) PAL-434 211–410 19–54.4 26–46.8 SNDRA Cathinone [5][93][121][112][107][126][107]
3-CPC PAL-363 IA ND IA (RI) ND Cathinone [107]
3′-CPM PAL-594 301 75
(82% at 10 μM)		 27
(100% at 10 μM)		 ND Phenylmorpholine [125][117]
3-FA PAL-353 1937 16.1 24.2 NDRA Amphetamine [127][4]
3-FMC ND 1460 ND
(100% at 10 μM)		 64.8 NDRA Cathinone [93]
3′-FPM PAL-593 1269–2558 17–30 43–60 NDRA Phenylmorpholine [115][117]
3-MA PAL-314 218 18.3 33.3 NDRA Amphetamine [127][81][4]
3-MCPC PAL-588 1067 ND IA (RI) ND Cathinone [107]
3-MeO-A ND ND 58.0 103 ND Amphetamine [4]
3-MeO-CPC PAL-591 1014 ND IA (RI) ND Cathinone [107]
3-MeO-MC ND 306–683 111
(68% at 10 μM)		 109–129 SNDRA Cathinone [93][121][112]
3-MeO-PM PAL-823 ND
(78% at 10 μM)		 ND
(86% at 10 μM)		 ND
(96% at 10 μM)		 ND Phenylmorpholine [117]
3-MMC ND 268–292 27 28–70.6 SNDRA Cathinone [5][93][121][112]
3-MPM PAL-773 86 62 227 SNDRA Phenylmorpholine [116]
3-TFMeO-MC ND 188 ND
(79% at 10 μM)		 729 SNDRA Cathinone [93]
3-TFMMC (3-TFMAP) ND 297–380 2700
(78% at 10 μM)		 610–1290 SNDRA Cathinone [118][93][119][112]
3,4-DCCPC PAL-787 356 ND IA (RI) ND Cathinone [107]
4-APBT ND 21.2 46.2 66.6 SNDRA APBT [74]
4-Benzylpiperidine ND 5246 41.4 109 NDRA Benzylpiperidine [128]
4-BMC (brephedrone) ND 42.5–60.2 100 59.4 SNDRA Cathinone [129][93][121][112][130][131]
4-CA (PCA) ND 28.3 23.5–26.2 42.2–68.5 SNDRA Amphetamine [81][4][132][133]
4-CC ND 128.4 85.1 221.8 SNDRA Cathinone [132]
4-CCPC PAL-743 1632 ND IA (RI) ND Cathinone [107]
4-CEA (PCEA) ND 33.8 162.6 238.0 SNDRA Amphetamine [132][133]
4-CEC ND 152.6 5194.0 353.6 SDRA Cathinone [132]
4-CMA (PCMA) ND 29.9 36.5 54.7 SNDRA Amphetamine [132][133]
4-CMC (clephedrone) ND 71.1–144 44–90.9 42.2–74.7 SNDRA Cathinone [129][93][132][121][112][130][131]
4-Et-PEA PAL-505 ND ND 2087 ND Phenethylamine [5]
4-FA PAL-303 730–939 28.0–37 51.5–200 NDRA Amphetamine [127][66][81][4]
4-Fluoro-T PAL-551 108 1123 106 SDRA Tryptamine [11]
4-FMC (flephedrone) ND 1290–1450 62 83.4–119 NDRA Cathinone [129][93][121][130][131]
4-FPM PAL-635 2403
(88% at 10 μM)		 285
(100% at 10 μM)		 529
(95% at 10 μM)		 SNDRA Phenylmorpholine [117]
4′-FPM PAL-748 1895 58 191 NDRA Phenylmorpholine [115][117]
4-iPr-PEA PAL-595 ND ND IA ND Phenethylamine [5]
4-MA PAL-313 53.4 22.2 44.1 SNDRA Amphetamine [127][81][4]
4-MAR ND ND ND ND ND Phenyloxazolamine [110]
  cis-4-MAR ND 53.2 4.8 1.7 NDRA Phenyloxazolamine [110][134]
4-MBA ND IA IA IA IA Amphetamine [135]
4-MCPC PAL-744 667 ND IA (RI) ND Cathinone [107]
4-MEA ND 102 182 550 SNDRA Amphetamine [135]
4-MeO-MC (methedrone) ND 120–195 111 506–881 SNDRA Cathinone [129][93][121][112][130][131]
4-MeO-T PAL-548 4114 >10000 >10000 SRA Tryptamine [11]
4-MMA ND 67.4 66.9 41.3 SNDRA Amphetamine [135][130]
4-MPA ND 650 752 IA SNRA Amphetamine [135]
4-MPEA (4-Me-PEA) PAL-503 ND ND 271 ND Phenethylamine [5]
4-MPM PAL-747 86 62 227 SNDRA Phenylmorpholine [116][117]
4-MTA ND ND ND ND SNDRA Amphetamine [136][137][138]
4-MTMA PAL-1063 21 ND ND SNDRA Amphetamine [78]
4-tBu-MC ND IA ND 942
(EmaxTooltip maximal efficacy ≈ 50%)		 ND Cathinone [139]
4-TFMeO-MC ND 118 ND 7510 ND Cathinone [93]
4-TFMMC (4-TFMAP) ND 190–270 900 2700–4230 SNRA Cathinone [140][129][118][119][131][112]
4,4'-DMAR ND ND ND ND SNDRA Phenyloxazolamine ND
  cis-4,4'-DMAR ND 17.7–59.9 11.8–31.6 8.6–24.4 SNDRA Phenyloxazolamine [134][141][110]
  trans-4,4'-DMAR ND 59.9 31.6 24.4 SNDRA Phenyloxazolamine [141][110]
5-APB ND 19 21 31 SNDRA Amphetamine [70]
5-APBT ND 10.3 38.4 92.8 SNDRA APBT [74]
5-API (5-IT) PAL-571 28–104.8 13.3–79 12.9–173 SNDRA Amphetamine [12][76]
5-Bromo-T PAL-518 75.0 >10000 478 SDRA Tryptamine [11]
5-Chloro-αET PAL-526 33.2 >10000 IA (RI) SRA α-Ethyltryptamine [11]
5-Chloro-αMT PAL-542 16.2 3434 54.3 SDRA α-Methyltryptamine [11][12]
5-Chloro-T PAL-441 19.1 >10000 476 SRA Tryptamine [11]
5-Fluoro-αET PAL-545 36.6 5334 150 SDRA α-Ethyltryptamine [11]
5-Fluoro-αMT PAL-544
PAL-212		 14–19 78–126 32–37 SNDRA α-Methyltryptamine [12][11][42]
5-Fluoro-T PAL-284 10.1 464 82.3 SDRA Tryptamine [11]
5-MABB (5-MBPB) ND ND ND ND ND Amphetamine [73][142]
  (S)-5-MABB ND 31 158 210 SNDRA Amphetamine [73][142]
  (R)-5-MABB ND 49 850 IA SRA Amphetamine [73][142]
5-MAPB ND 64–90 24 41–459 SNDRA Amphetamine [70][143]
  (S)-5-MAPB ND 67 ND 258 ND Amphetamine [143]
  (R)-5-MAPB ND 184 ND 1951 ND Amphetamine [143]
5-MeO-αMT ND 460 8900 1500 SNDRA α-Methyltryptamine [66]
5-MeO-DALT ND >100000 >100000 >100000 IA Tryptamine [66]
5-MeO-DET ND IA (RI) IA IA SRI Tryptamine [42]
5-MeO-DiPT ND >100000 (RI) >100000 (RI) >100000 IA Tryptamine [66][42]
5-MeO-DMT ND >100000 (RI) >100000 (RI) >100000 IA Tryptamine [66][42]
5-MeO-DPT ND IA (RI) IA IA (RI) SRI Tryptamine [42]
5-MeO-MiPT ND >100000 >100000 >100000 IA Tryptamine [66][42]
5-MeO-NET ND 284 >10000 >10000 SRA Tryptamine [42]
5-MeO-NiPT ND IA (RI) IA IA SRI Tryptamine [42]
5-MeO-NMT ND 1114 >10000 >10000 SRA Tryptamine [42]
5-MeO-T PAL-234 2169 >10000 11031 SDRA Tryptamine [11][42]
5-Methyl-T PAL-22 139 >10000 >10000 SRA Tryptamine [11]
6-APB ND 36 14 10 SNDRA Amphetamine [70]
6-APBT ND 10.7 13.6 7.2 SNDRA APBT [74]
6-API (6-IT) ND 19.9 25.6 164.0 SNDRA Amphetamine [76]
6-Fluoro-T PAL-227 4.4 1575 106 SRA Tryptamine [11]
6-MABB (6-MBPB) ND ND ND ND ND Amphetamine [73][142]
  (R)-6-MABB ND 172 227 IA SNRA Amphetamine [73][142]
  (S)-6-MABB ND 54 77 41 SNDRA Amphetamine [73][142]
6-MAPB ND 33 14 20 SNDRA Amphetamine [70]
6-MeO-T PAL-263 53.8 465 113 SNDRA Tryptamine [11]
6-Methyl-T PAL-522 51.6 >10000 353 SDRA Tryptamine [11]
7-APBT ND 36.9 28.5 16.8 SNDRA APBT [74]
7-Chloro-T PAL-532 8.03 656 1330 SRA Tryptamine [11]
7-MeO-T PAL-533 44.6 5600 2118 SRA Tryptamine [11]
7-Methyl-T PAL-286 23.7 >10000 3380 SRA Tryptamine [11]
α-Ethyltryptamine (AET, αET) PAL-125 23.2 640 232 SDRA α-Ethyltryptamine [11]
  (–)-α-Ethyltryptamine PAL-640 54.9 3670 654 SRA α-Ethyltryptamine [11]
  (+)-α-Ethyltryptamine PAL-647 34.7 592 57.6 SDRA α-Ethyltryptamine [11]
α-Me-MC (βk-mephentermine; RAD-081) ND 12860 153 590 NDRA Cathinone [144][145][146]
α-Methylisotryptamine (isoAMT) PAL-569 177 81 1062 SNRA Isotryptamine [12]
α-Methyltryptamine (αMT; AMT) PAL-17 21.7–68 79–112 78.6–180 SNDRA α-Methyltryptamine [66][11][147]
βk-NMPEA (FTS-096) ND >60000 148 1860 NRA Phenethylamine [144][145][146]
AMAPN ND 21 ND 55 ND Cathinone [93][148]
Amfepramone (diethylpropion) ND >10000 >10000 >10000 PD Cathinone [149][106]
Aminorex ND 193–414 15.1–26.4 9.1–49.4 SNDRA Phenyloxazolamine [41][134][4][110][106]
Amphetamine (A) ND ND ND ND NDRA Amphetamine ND
  Dextroamphetamine ND 698–1765 6.6–10.2 5.8–24.8 NDRA Amphetamine [41][150][4][139][106]
  Levoamphetamine ND ND 9.5 27.7 NDRA Amphetamine [81][4][151][152]
APPEA (α-Pr-PEA) PAL-550 IA ND IA (RI) ND Amphetamine [5][107]
BDB ND 180 540 2,300 NDRA Amphetamine [66]
Benzylpiperazine (BZP) ND 6050–>10000 62–68 175–600 NDRA Phenylpiperazine [66][153][3][4][154]
BK-NM-AMT ND 41.3 ND
(55% at 10 μM)		 92.8 SDRA α-Methyltryptamine [93][148][94]
BK-5F-NM-AMT ND 190 ND 620 ND α-Methyltryptamine [155]
BK-5Cl-NM-AMT ND 200 ND 865 ND α-Methyltryptamine [155]
BK-5Br-NM-AMT ND 295 ND 2100 ND α-Methyltryptamine [155]
BMAPN ND 27 ND 34 ND Cathinone [93][148]
BMPEA (β-Me-PEA) ND ND 126 627 ND Phenethylamine [156]
Bufotenin (DMS, 5-HO-DMT) ND 30.5 >10000 >10000 SRA Tryptamine [42]
Buphedrone (βk-MEPEA) PAL-429 IA ND 411 ND Cathinone [107]
Bupropion (amfebutamone) ND IA (RI) IA (RI) IA (RI) NDRI Cathinone [146][123][121]
Butylamphetamine (NBA, BA) PAL-90 ND ND IA ND Amphetamine [5]
Butylone (βk-MBDB) ND 330 IA (RI) IA (RI) SRA/NDRI Cathinone [157][158]
Cathinone (C; βk-AMPH) ND 6100–7595 23.6–25.6 34.8–83.1 NDRA Cathinone [4][93][132]
  D-Cathinone ND >10000 72.0 183.9 NDRA Cathinone [159]
  L-Cathinone ND 2366–9267 12.4–28 18–24.6 NDRA Cathinone [160][123][159]
Chlorphentermine ND 18.2–30.9 >10000 (RI) 935–2650 SRA Amphetamine [41][106]
DEPEA (α-Et-EPEA) ND ND 209 604 ND Amphetamine [161]
Dibutylone ND IA IA (RI) IA (RI) DRI Cathinone [162]
Diethyltryptamine (DET) ND IA (RI) IA IA SRI Tryptamine [42]
Diisopropyltryptamine (DiPT) ND IA (RI) IA (RI) IA SRI Tryptamine [42]
Dimethylamphetamine ND ND 223 1250 ND Amphetamine [156]
Dimethyltryptamine (DMT) ND 114 4166 >10000 SRA Tryptamine [42]
Dipropyltryptamine (DPT) ND >100000 (RI) >100000 (RI) >100000 (RI) IA Tryptamine [66][42]
DMPP (2,3-DMPP) PAL-218 24–26 13.7–56 1207–1320 SNRA Phenylpiperazine [78][86]
DOC ND IA IA IA IA Amphetamine [120]
Dopamine (DA) ND >10000 (RI) 66.2 86.9 NDRA Phenethylamine [41][4]
EDMA ND 117 325 597 SNDRA Amphetamine [67][130]
EDMC ND 347 327 496 SNDRA Cathinone [67][130]
ENAP PAL-1045 12 137 46 SDRA Amphetamine [78]
Ephedrine (racephedrine) ND ND ND ND NDRA Cathinol ND
  D-Ephedrine (ephedrine) ND >10000 43.1–72.4 236–1350 NDRA Cathinol [41][4]
  L-Ephedrine ND >10000 218 2104 NRA Cathinol [41][160]
Ephylone ND IA (RI) IA (RI) IA (RI) IA (NDRI) Cathinone [163]
Epinephrine ND ND ND ND NDRA Phenethylamine ND
Ethcathinone (EC) ND 1923–2118 88.3–99.3 267.6–>1000 NRA Cathinone [149][4][132][139]
Ethylamphetamine (EA) PAL-99 ND ND 88.5 ND Amphetamine [5]
  S(+)-Ethylamphetamine ND 333.0 28.8 44.1 NDRA Amphetamine [132][133]
Ethylone (βk-MDEA) ND 617.4 4251 1122 SNDRA Cathinone [130]
Eutylone (βk-EBDB) ND 1020 IA (RI) IA (RI) SRA/NDRI Cathinone [162]
Fenfluramine (3-TFM-EA) ND 79.3–108 739 >10000 (RI) SRA Amphetamine [41][164][165][4]
  D-Fenfluramine ND 51.7 302 >10000 SNRA Amphetamine [41][164]
  L-Fenfluramine ND 147 >10000 >10000 SRA Amphetamine [164][166]
HHA ND ND 33 3485 ND Amphetamine [4]
HHMA ND 1729 77 130 NDRA Amphetamine [4][167]
HHMC ND 14100 110 90 NDRA Cathinone [168]
HMA ND 897 694 1450–3423 SNDRA Amphetamine [4][169][170]
HMMA ND 589–607 625 607–3652 SNDRA Amphetamine [4][169][170][167]
HMMC ND 7210 6340 5840 SNDRA Cathinone [168]
MBDB ND 540 3300 >100000 SNRA Amphetamine [66]
mCPP (3-CPP, 3CPP) ND 28–38.1 ≥1400 63000 SRA Phenylpiperazine [66][166][171]
MDA ND 160–162 47–108 106–190 SNDRA Amphetamine [165][4][70]
  (R)-MDA ND 310 290 900 SNDRA Amphetamine [165][4]
  (S)-MDA ND 100 50.0 98.5 SNDRA Amphetamine [165][4]
MDAI ND 114 117 1334 SNRA Aminoindane [87]
MDC ND 966 394 370 SNDRA Cathinone [168]
MDEA PAL-192 47 2608 622 SNDRA Amphetamine [78]
  (R)-MDEA PAL-193 52 651 507 SNDRA Amphetamine [78]
  (S)-MDEA PAL-194 465 RI RI SRA Amphetamine [78]
MDMA ND 50–85 54–110 51–278 SNDRA Amphetamine [41][172][76][165][4][70]
  (R)-MDMA ND 340 560 3700 SNDRA Amphetamine [165][4]
  (S)-MDMA ND 74 136 142 SNDRA Amphetamine [165][4]
MDMAR ND ND ND ND SNDRA Phenyloxazolamine ND
  cis-MDMAR ND 43.9 14.8 10.2 SNDRA Phenyloxazolamine [141]
  trans-MDMAR ND 73.4 38.9 36.2 SNDRA Phenyloxazolamine [141]
MDPV ND IA 13
(EmaxTooltip maximal efficacy = 24%)		 2.3
(Emax = 24%)		 NDRI Phenylethylpyrrolidine [150][130]
MEAI (5-MeO-AI) ND 134 861 2646 SNRA Aminoindane [87]
MEPEA (α-Et-MPEA) PAL-426 4698 58 179–225 SNDRA Amphetamine [107][161]
Mephedrone (4-MMC) ND 118.3–122 58–62.7 49.1–51 SNDRA Cathinone [172][150][93][112][131]
  S(–)-Mephedrone ND 61 ND 74 ND Cathinone [139][173]
  R(+)-Mephedrone ND 1470 ND 31 ND Cathinone [139][173]
Mesocarb ND ND ND >100000 (RI) DRI Amphetamine [174]
Methamphetamine (MA) ND ND ND ND NDRA Amphetamine ND
  Dextromethamphetamine ND 736–1292 12.3–14.3 8.5–40.4 NDRA Amphetamine [41][172][4][106]
  Levomethamphetamine ND 4640 28.5 416 NRA Amphetamine [41][4]
Methcathinone (MC) ND 2592–5853 22–26.1 12.5–49.9 NDRA Cathinone [4][93][121][112][132]
  D-Methcathinone ND IA ND ND NRA Cathinone [146]
  L-Methcathinone ND 1772 13.1 14.8 NDRA Cathinone [160][139]
Methiopropamine ND IA (RI) IA (RI) IA (RI) NDRI Thiopropamine [175][176]
Methylone (MDMC) ND 234–708 140–270 117–220 SNDRA Cathinone [172][150][130][162][168]
Methylphenidate ND IA (RI) IA (RI) IA (RI) NDRI Phenidate [3][52][177]
Mexedrone (4-MMC-MeO) ND 2525 IA (RI) IA (RI) SRA/NDRI Cathinone [178]
MiPT ND IA IA IA IA Tryptamine [42]
MMAI ND 31 3101 >10000 SRA Aminoindane [87]
MNAP (methamnetamine) PAL-1046 13 34 10 SNDRA Amphetamine [78][5]
MPPA (BMMPEA, β-Me-NMPEA) ND ND 154 574 ND Phenethylamine [156]
Naphthylisopropylamine (NAP) PAL-287 3.4 11.1 12.6 SNDRA Amphetamine [179][4]
Naphthylmetrazine PAL-704 IA (RI 203 111 NDRA/SRI Phenylmorpholine [117]
Naphthylmorpholine PAL-678 ND
(92% at 10 μM)		 ND
(88% at 10 μM)		 ND
(79% at 10 μM)		 ND Phenylmorpholine [117]
NET (NETP; N-Et-T) PAL-536 18.6 IA (RI) IA (RI) SRA Tryptamine [11][42]
NiPT ND IA (RI) IA IA SRI Tryptamine [42]
NMT PAL-152 22.4 733 321 SRA Tryptamine [11][42]
Norephedrine (phenylpropanolamine) ND ND ND ND NDRA Cathinol ND
  D-Norephedrine ND >10000 42.1 302 NDRA Cathinol [160]
  L-Norephedrine ND >10000 137 1371 NRA Cathinol [160]
Norepinephrine (NE) ND >10000 164 869 NDRA Phenethylamine [41][4]
Norfenfluramine (3-TFMA) ND 104 168–170 1900–1925 SNRA Amphetamine [164][165]
  (+)-Norfenfluramine ND 59.3 72.7 924 SNRA Amphetamine [164]
  (–)-Norfenfluramine ND 287 474 >10000 SNRA Amphetamine [164]
Normephedrone (4-MC) ND 210 100 220 SNDRA Cathinone [180][159][139]
  R(+)-Normephedrone ND 179 89 150 SNDRA Cathinone [139][159]
  S(–)-Normephedrone ND 1592 115 391 NDRA Cathinone [139][159]
Norpropylhexedrine ND ND ND ND NDRA Cyclohexylethylamine ND
Norpseudoephedrine ND ND ND ND NDRA Cathinol ND
  D-Norpseudoephedrine (cathine) ND >10000 15.0 68.3 NDRA Cathinol [160]
  L-Norpseudoephedrine ND >10000 30.1 294 NDRA Cathinol [160]
ODMA ND ND ND ND SNDRA Amphetamine [80]
oMPP (2-MPP) PAL-169 175 39.1 296–542 SNDRA Phenylpiperazine [181][5][86]
PMA (4-MeO-A) ND ND 166 867 SNDRA Amphetamine [4][92][138]
PMMA (4-MeO-MA) ND ND ND ND SNDRA Amphetamine [138]
  (S)-PMMA ND 41 147 1000 SNRA Amphetamine [140][182][92]
  (R)-PMMA ND 134 >14000 1600 SRA Amphetamine [140][182][92]
Pentylone ND 476–1030
(EmaxTooltip maximal efficacy ≈ 50%)		 IA (RI) IA (RI) SRA/NDRI Cathinone [157][162][163]
Phenacylamine (βk-PEA) PAL-27 >10000 ND
(96% at 10 μM)		 208 NDRA Phenethylamine [5][93][139]
Phendimetrazine ND >100000 >10000 >10000 PD Phenylmorpholine [183][4][106]
Phenethylamine (PEA) ND >10000 10.9 39.5 NDRA Phenethylamine [5][81][4]
Phenmetrazine (PM) PAL-55 7765–>10000 29–50.4 70–131 NDRA Phenylmorpholine [183][4][116][117]
Phentermine (P, PH) ND 2575–3511 28.8–39.4 262 NDRA Amphetamine [41][4][106]
Phenylalaninol ND ND ND ND ND Amphetamine ND
  D-Phenylalaninol PAL-329 >10000 106 1355 NRA Amphetamine [181]
Phenylbutenamine ND ND ND ND ND Phenylbutenamine ND
  (3E)-Phenylbutenamine PAL-881 >10000 308 666 SNRA Phenylbutenamine [82][83]
  (3Z)-Phenylbutenamine PAL-893 >10000 301 1114 SNRA Phenylbutenamine [82][83]
Phenylbutynamine PAL-874 >10000 305 688 NDRA Phenylbutynamine [78]
Phenylisobutylamine (α-Et-PEA, AEPEA) PAL-426 4698 80 225–273 NDRA Amphetamine [5][107][122][161]
Phenylpropylamine ND ND 222 1491 NDRA Phenylpropylamine [81][4]
pMeOPP (4-MeOPP) ND 3200 440–1500 6300–11000 SNRA Phenylpiperazine [66][86]
pMPP (4-MPP) PAL-233 ND ND IA (RI) ND Phenylpiperazine [5]
pNPP (4-NPP) PAL-175 19–43
(EmaxTooltip maximal efficacy = 57%)		 >10000 >10000 SRA Phenylpiperazine [78][86]
Propylamphetamine (PA) PAL-424 ND ND RI (1013) ND Amphetamine [5]
Propylcathinone (PC) PAL-359 ND ND IA ND Cathinone [5][139]
Propylhexedrine ND ND ND ND NDRA Cyclohexylethylamine ND
Propylone ND 3128 IA (RI) 975.9 SDRA Cathinone [130]
Pseudoephedrine (racemic) ND ND ND ND NDRA Cathinol ND
  D-Pseudoephedrine ND >10000 4092 9125 NDRA Cathinol [160]
  L-Pseudoephedrine (pseudoephedrine) ND >10000 224 1988 NRA Cathinol [160]
Pseudophenmetrazine ND >10000 514 RI NRA Phenylmorpholine [183]
Psilocin PAL-153 561
(EmaxTooltip maximal efficacy = 54%)		 >10000 >10000 SRA Tryptamine [78][42]
SeDMA ND ND ND ND SNDRA Amphetamine [80]
Serotonin (5-HT) ND 44.4 >10000 (RI) ≥1960 SRA Tryptamine [41][4]
TDMA ND ND ND ND SNDRA Amphetamine [80]
TFMCPP (3-TFM-4-C-PP) PAL-179 33
(EmaxTooltip maximal efficacy = 66%)		 >10000 >10000 SRA Phenylpiperazine [78]
TFMPP (3-TFMPP) ND 121 >10000 >10000 SRA Phenylpiperazine [153][154][4]
TMA (3,4,5-TMeO-A) ND 16000 >100000 >100000 IA Amphetamine [66]
TMA-2 (2,4,5-TMeO-A) ND >100000 >100000 >100000 IA Amphetamine [66]
TMA-6 (2,4,6-TMeO-A) ND >100000 >100000 >100000 IA Amphetamine [66]
Tramadol ND IA (RI) IA (RI) IA SNRI ND [3]
Tryptamine (T) PAL-235 32.6 716 164 SDRA Tryptamine [42][11]
Tyramine ND 2775 40.6 119 NDRA Phenethylamine [41][4]
Notes: (1) The smaller the value, the more potently the substance releases the neurotransmitter. (2) These values were from assays conducted using rat brain synaptosomes. Values from other methods of quantifying monoamine release, such as HEK293 cells transfected with monoamine transporters, are not fully analogous to neuronal cells and result in much different and lower potencies. As a result, they are not included in this table.

References

[edit]
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