Monoamine releasing agent explained

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.[1] [2] [3] [4] [5] The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; monoamine releasing agents can induce the release of one or more of these neurotransmitters.

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. 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.

A variety of different classes of drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters. 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. Trace amines like phenethylamine and tryptamine, as well as the monoamine neurotransmitters themselves, are endogenous monoamine releasing agents. It is thought that monoamine release by endogenous mediators may play some physiological regulatory role.

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.

Types and selectivity

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

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

Effects and uses

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

Selective SRAs such as chlorphentermine have been described as dysphoric and lethargic.[7] [8] 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.[9] 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.[10]

DRAs, usually non-selective for both norepinephrine and dopamine, have psychostimulant effects, causing an increase in energy, motivation, elevated mood, and euphoria.[11] Other variables can significantly affect the subjective effects, such as infusion rate (increasing positive effects of DRAs) and psychological expectancy effects.[12] 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.[13] They may also be performance-enhancing,[14] in contrast to reboxetine which is solely a norepinephrine reuptake inhibitor.[15] [16] 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).[17] 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,[18] [19] [20] 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. Moreover, amphetamines continue to produce psychostimulant-like effects and induction of dopamine and norepinephrine release in TAAR1 knockout mice.[21] [22] [23] In fact, TAAR1 knockout mice are supersensitive to the effects of amphetamines and TAAR1 activation appears to inhibit the striatal dopaminergic effects of psychostimulants.[24] 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.[25] [26] [27] [28]

There is a constrained and relatively small molecular size requirement for compounds to act as monoamine releasing agents. 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. Compounds with chemical features extending beyond the size constraints for releasers will instead act as partial releasers, reuptake inhibitors, or be inactive. Partial releasers show reduced maximal efficacy in releasing monoamine neurotransmitters compared to conventional full releasers.

Other related agents

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.[29] [30] [31] 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. A variety of different pieces of evidence support this hypothesis and help to explain otherwise confusing findings. 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. 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.[32]

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).[33] [34] [35] 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). They are usually active as MAEs at much lower concentrations than those at which they induce monoamine release. The MAE actions of MAEs may be mediated by TAAR1 agonism, which has likewise been implicated in monoamine-releasing actions.[36] [37] MAEs without concomitant potent monoamine-releasing actions, like selegiline (L-deprenyl), phenylpropylaminopentane (PPAP), and benzofuranylpropylaminopentane (BPAP), have been developed.

Endogenous MRAs

A number of endogenous compounds are known to act as MRAs. These include the monoamine neurotransmitters dopamine (an NDRA), norepinephrine (an NDRA), and serotonin (an SRA) themselves, as well as the trace amines phenethylamine (an NDRA),[38] [39] tryptamine (an SDRA or imbalanced SNDRA), and tyramine (an NDRA). Synthetic MRAs are substantially based on structural modification of these endogenous compounds, most prominently including the substituted phenethylamines and substituted tryptamines.[40] [41] [42]

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

It is possible monoamine neurotransmitter self-release could be a protective mechanism. 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.[43] [44] [45] Along similar lines, monoamine releasing agents induce the efflux of non-vesicular monoamine neurotransmitter and thereby move cytoplasmic neurotransmitter into the extracellular space. 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.

Monoaminergic neurotoxicity

See main article: Monoaminergic neurotoxin.

Some MRAs have been found to act as monoaminergic neurotoxins and hence to produce long-lasting damage to monoaminergic neurons.[46] [47] Examples include dopaminergic neurotoxicity with amphetamine and methamphetamine and serotonergic neurotoxicity with methylenedioxymethamphetamine (MDMA). Amphetamine may produce significant dopaminergic neurotoxicity even at therapeutic doses.[48] [49] [50] [51] [52] [53] However, clinical doses of amphetamine producing neurotoxicity is controversial and disputed.[54] In contrast to amphetamines, monoamine reuptake inhibitors like methylphenidate lack apparent neurotoxic effects.

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.[55] [56] Certain drugs have been found to block the neurotoxicity of MRAs in animals. For instance, the selective MAO-B inhibitor selegiline has been found to prevent the serotonergic neurotoxicity of MDMA in rodents.

Activity profiles

Compound data-sort-type="number" !data-sort-type="number" !data-sort-type="number" !Type Class Ref
1-Naphthylmethcathinone (AMAPN) 21 55 Cathinone [57]
1-Phenylpiperazine (PP) 880 186 2530 SNRA [58]
2-Aminoindane (2-AI) >10000 86 439 NDRA [59]
8.9 21.6 38.6 SNDRA [60]
2-Bromomethcathinone (2-BMC) 2837 156 650 NDRA Cathinone
2-Chloromethcathinone (2-CMC) 2815 93 179 NDRA Cathinone
2-Fluoromethamphetamine (2-FMA) ~15000 <100 ~90 NDRA Amphetamine [61] [62]
2-Fluoromethcathinone (2-FMC) >10000
48.7 NDRA Cathinone
2-Methoxymethcathinone (2-MeOMC) 7220 339 920 NDRA Cathinone
2-Methylmethcathinone (2-MMC) 347–490 53 81–97.9 SNDRA Cathinone
2-Naphthylmethcathinone (BMAPN) 27 34 Cathinone
2,4,5-Trimethoxyamphetamine (TMA-2) >100000 >100000 >100000 Amphetamine
2,4,6-Trimethoxyamphetamine (TMA-6) >100000 >100000 >100000 Amphetamine
>100000 >100000 100000
Phenethylamine
>100000 >100000 >100000 Phenethylamine [63]
>100000 >100000 >100000 Phenethylamine
Phenethylamine
21.9 13.4 21.7 SNDRA
3-Bromomethcathinone (3-BMC) 136–137 25 21–28.0 Cathinone
3-Chloroamphetamine (3-CA) 120 9.4 11.8 SNDRA Amphetamine [64]
3-Chloromethcathinone (3-CMC) 211–410 19–54.4 26–46.8 SNDRA Cathinone [65]
3-Fluoroamphetamine (3-FA) 1937 16.1 24.2 NDRA [66]
3-Fluoromethcathinone (3-FMC) 1460
64.8 Cathinone
3-Methoxyamphetamine (3-MeOA) 58.0 103 Amphetamine
3-Methoxy-4-hydroxymethamphetamine (HMMA) 589 625 607–2884 SNDRA Amphetamine [67]
3-Methoxymethcathinone (3-MeOMC) 306–683 111
109–129 SNDRA Cathinone
3-Methylamphetamine (3-MA) 218 18.3 33.3 NDRA Amphetamine
3-Methylmethcathinone (3-MMC) 268–292 27 28–70.6 SNDRA Cathinone
3,4-Dihydroxyamphetamine (HHA) 33 3485 Amphetamine
3,4-Dihydroxymethamphetamine (HHMA) 77 1729 Amphetamine
3,4,5-Trimethoxyamphetamine (TMA) 16000 >100000 >100000 Amphetamine
21.2 46.2 66.6 SNDRA
5246 41.4 109 NDRA [68]
4-Bromomethcathinone (4-BMC; brephedrone) 42.5–60.2 100 59.4 Cathinone
4-Chloroamphetamine (4-CA; PCA) 28.3 23.5–26.2 42.2–68.5 SNDRA Amphetamine
4-Chloromethamphetamine (4-CMA; PCMA; clephedrone) 29.9 36.5 54.7 SNDRA Amphetamine
4-Chloroethylamphetamine (4-CEA; PCEA) 33.8 162.6 238.0 SNDRA Amphetamine
4-Chlorocathinone (4-CC) 128.4 85.1 221.8 SNDRA Cathinone
4-Chloromethcathinone (4-CMC) 71.1–144 44–90.9 42.2–74.7 SNDRA Cathinone
4-Chloroethcathinone (4-CEC) 152.6 5194.0 353.6 SDRA Cathinone
4-Fluoroamphetamine (4-FA) 730–939 28.0–37 51.5–200 NDRA Amphetamine
4-Fluoromethcathinone (4-FMC; flephedrone) 1290–1450 62 83.4–119 Cathinone
4-Hydroxy-3-methoxyamphetamine (HMA) 897 694 1450–3423 Amphetamine
4-Methoxyamphetamine (4-MeOA) 166 867 Amphetamine
4-Methoxymethcathinone (4-MeOMC; methedrone) 120–195 111 506–881 Cathinone
53.2 4.8 1.7 NDRA [69]
4-Methylamphetamine (4-MA) 53.4 22.2 44.1 SNDRA Amphetamine
4-Methylmethamphetamine (4-MMA) 67.4 66.9 41.3 SNDRA Amphetamine [70]
4-Methylphenethylamine (4-MPEA) 271 Phenethylamine
4-Methylthiomethamphetamine (4-MTMA) 21 Amphetamine [71]
4,4'-Dimethylaminorex (4,4'-DMAR) SNDRA Aminorex
cis-4,4'-Dimethylaminorex 17.7–18.5 11.8–26.9 8.6–10.9 SNDRA Aminorex [72]
trans-4,4'-Dimethylaminorex 59.9 31.6 24.4 SNDRA Aminorex
19 21 31 SNDRA Amphetamine [73]
10.3 38.4 92.8 SNDRA
5-(2-Aminopropyl)indole (5-IT) 28–104.8 13.3–79 12.9–173 SNDRA Amphetamine [74] [75]
33.2 >10000 SRA
16.2 3434 54.3 SDRA Tryptamine
36.6 5334 150 SDRA Tryptamine
14–19 78–126 32–37 SNDRA Tryptamine
5-MABB (5-MBPB) Amphetamine
(S)-5-MABB 31 158 210 SNDRA Amphetamine
(R)-5-MABB 49 850 SRAAmphetamine
64–90 24 41–459 SNDRA Amphetamine [76]
(S)-5-MAPB 67 258 Amphetamine
(R)-5-MAPB 184 1951 Amphetamine
460 8900 1500 SNDRA Tryptamine [77]
134 861 2646 SNRA Aminoindane
>100000 >100000 >100000 Tryptamine
>100000 >100000 >100000 Tryptamine
>100000 >100000 >100000 Tryptamine
>100000 >100000 >100000 Tryptamine
36 14 10 SNDRA Amphetamine
10.7 13.6 7.2 SNDRA
6-(2-Aminopropyl)indole (6-IT) 19.9 25.6 164.0 SNDRA Amphetamine
6-Chloroamphetamine (6-CA) 19.1 62.4 Amphetamine
6-Fluoroamphetamine (6-FA) 24.1 38.1 Amphetamine
6-MABB (6-MBPB) Amphetamine [78] [79]
(R)-6-MABB 172 227 SNRA Amphetamine
(S)-6-MABB 54 77 41 SNDRA Amphetamine
33 14 20 SNDRA Amphetamine
6-Methoxyamphetamine (6-MeOA) 473 1478 Amphetamine
6-Methylamphetamine (6-MA) 37 127 Amphetamine
36.9 28.5 16.8 SNDRA
α-Ethyltryptamine (αET; AET) 23.2 640 232 SDRA Tryptamine
(–)-α-Ethyltryptamine 54.9 3670 654 SRA Tryptamine
(+)-α-Ethyltryptamine 34.7 592 57.6 SDRA Tryptamine
α-Methylisotryptamine (isoAMT) 177 81 1062 SNRA
α-Methyltryptamine (αMT; AMT) 21.7–68 79–112 78.6–180 SNDRA Tryptamine
β-Methylphenethylamine (BMPEA) 126 627 Phenethylamine
β,N-Dimethylphenethylamine (MPPA, BMMPEA) 154 574 Phenethylamine
>10000 >10000 >10000 [80]
193–414 15.1–26.4 9.1–49.4 SNDRA Aminorex [81]
NDRA Amphetamine
698–1765 6.6–10.2 5.8–24.8 NDRA Amphetamine [82]
9.5 27.7 NDRA Amphetamine
180 540 2,300 NDRA Amphetamine
≥6050 62–68 175–600 NDRA [83]
41.3
92.8 SDRA Tryptamine [84] [85]
190 620 Tryptamine [86]
200 865 Tryptamine
295 2100 Tryptamine
30.5 >10000 >10000 SRA Tryptamine
NDRI Cathinone [87] [88]
Amphetamine
330 SRA/NDRI Cathinone [89] [90]
6100–7595 23.6–25.6 34.8–83.1 NDRA Cathinone
-Cathinone >10000 72.0 183.9 NDRA Cathinone [91]
-Cathinone 2366–9267 12.4–28 18–24.6 NDRA Cathinone
30.9 >10000 2650 SRA Amphetamine
DRI Cathinone
223 1250 Amphetamine [92]
Dimethyltryptamine (DMT) 114 4166 >10000 SRA Tryptamine
Amphetamine
Dipropyltryptamine (DPT) >100000 >100000 >100000 Tryptamine
26 56 1207 SNRA Arylpiperazine
>10000 66.2 86.9 NDRA Phenethylamine
117 325 597 SNDRA Amphetamine [93]
347 327 496 SNDRA Cathinone
Ephedrine (racephedrine) NDRA
-Ephedrine (ephedrine) >10000 43.1–72.4 236–1350 NDRA Cathinol
-Ephedrine >10000 218 2104 NRA Cathinol
(NDRI) Cathinone [94]
NDRA Phenethylamine
1923–2118 88.3–99.3 267.6–>1000 NRA Cathinone
88.5 Amphetamine
S(+)-Ethylamphetamine 333.0 28.8 44.1 NDRA Amphetamine [95]
617.4 4251 1122 SNDRA Cathinone
1020 SRA/NDRI Cathinone [96]
79.3–108 739 >10000 SRA Amphetamine [97] [98]
51.7 302 >10000 SNRA Amphetamine
147 >10000 >10000 SRA Amphetamine [99]
14100 110 90 NDRA Cathinone
7210 6340 5840 SNDRA Cathinone
540 3300 >100000 SNRA Amphetamine
28–38.1 ≥1400 63000 SRA Arylpiperazine [100]
160–162 47–108 106–190 SNDRA Amphetamine
(R)-MDA 310 290 900 SNDRA Amphetamine
(S)-MDA 100 50.0 98.5 SNDRA Amphetamine
Methylenedioxycathinone (MDC) 966 394 370 SNDRA Cathinone
114 117 1334 SNRA Aminoindane
47 2608 622 SNDRA Amphetamine
(R)-MDEA 52 651 507 SNDRA Amphetamine
(S)-MDEA 465 SRA Amphetamine
50–85 54–110 51–278 SNDRA Amphetamine [101]
340 560 3700 SNDRA Amphetamine
(S)-MDMA 74 136 142 SNDRA Amphetamine
SNDRA Aminorex
cis-MDMAR 43.9 14.8 10.2 SNDRA Aminorex
trans-MDMAR 73.4 38.9 36.2 SNDRA Aminorex
118.3–122 58–62.7 49.1–51 SNDRA Cathinone
13 34 10 SNDRA Amphetamine
NDRA Amphetamine
736–1291.7 12.3–13.8 8.5–24.5 NDRA Amphetamine
4640 28.5 416 NRA Amphetamine
2592–5853 22–26.1 12.5–49.9 NDRA Cathinone [102] [103]
-Methcathinone NRA Cathinone
-Methcathinone 1772 13.1 14.8 NDRA Cathinone
Methylenedioxypyrovalerone (MDPV) 13
(= 24%) 		2.3
(= 24%) 		NDRI [104]
Methylone (MDMC) 234–708 140–270 117–220 SNDRA Cathinone [105]
Mexedrone (4-MMC-MeO) 2525 SRA/NDRI Cathinone [106]
31 3101 >10000 SRA Aminoindane
567 105 64 SNDRA Cathinone
212 40 29 SNDRA Cathinone
N-Ethyltryptamine (NET) 18.6 SRA Tryptamine
N-Methyltryptamine (NMT) 22.4 733 321 SRA Tryptamine
3.4 11.1 12.6 SNDRA Amphetamine [107]
Norephedrine (phenylpropanolamine) NDRA Cathinol
-Norephedrine >10000 42.1 302 NDRA Cathinol [108]
-Norephedrine >10000 137 1371 NRA Cathinol
>10000 164 869 NDRA Phenethylamine
104 168–170 1900–1925 SNRA Amphetamine
(+)-Norfenfluramine 59.3 72.7 924 SNRA Amphetamine
(–)-Norfenfluramine 287 474 >10000 SNRA Amphetamine
Normephedrone (4-methylcathinone) 210 100 220 SNDRA Cathinone [109]
NDRA Cyclohexethylamine
NDRA Cathinol
-Norpseudoephedrine (cathine) >10000 15.0 68.3 NDRA Cathinol
>10000 30.1 294 NDRA Cathinol
175 39.1 296–542 SNDRA Arylpiperazine [110]
23 65 58 SNDRA
>10000 305 688 NDRA Phenylbutynamine
476–1030
(≈ 50%) 		SRA/NDRI Cathinone
Phenacylamine (β-ketophenethylamine) >10000 208 Phenethylamine
>100000 >10000 >10000 Phenylmorpholine [111]
>10000 10.9 39.5 NDRA Phenethylamine [112]
7765 50.4 131 NDRA Phenylmorpholine
3511 39.4 262 NDRA Amphetamine
Amphetamine
-Phenylalaninol >10000 106 1355 NRA Amphetamine
-Phenylalaninol Amphetamine
225 Amphetamine
222 1491 NDRA Phenylpropylamine
3200 1500 11000 SNRA Arylpiperazine
43 >10000 >10000 SRA Arylpiperazine
(1013) Amphetamine
NDRA Cyclohexethylamine
3128 975.9 SDRA Cathinone
Pseudoephedrine (racemic pseudoephedrine) NDRA Cathinol
>10000 4092 9125 NDRA Cathinol
-Pseudoephedrine (pseudoephedrine) >10000 224 1988 NRA Cathinol
>10000 514 NRA Phenylmorpholine
561 >10000 >10000 SRA Tryptamine
44.4 >10000 ≥1960 SRA Tryptamine
33 >10000 >10000 SRA Arylpiperazine
121 >10000 >10000 SRA Arylpiperazine
32.6 716 164 SDRA Tryptamine [113] [114]
2775 40.6 119 NDRA Phenethylamine
Notes: The smaller the value, the more strongly the substance releases the neurotransmitter.

Further reading

Notes and References

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  2. Rothman RB, Baumann MH . Therapeutic potential of monoamine transporter substrates . Current Topics in Medicinal Chemistry . 6 . 17 . 1845–1859 . 2006 . 17017961 . 10.2174/156802606778249766 .
  3. Book: Blough B . Dopamine-releasing agents . Dopamine Transporters: Chemistry, Biology and Pharmacology . 305–320 . July 2008 . 978-0-470-11790-3 . Wiley . Hoboken [NJ] . https://archive.today/20241104022653/https://archive.org/details/dopaminetranspor0000unse/page/310/mode/2up . 4 November 2024 . TABLE 11-2 Comparison of the DAT- and NET-Releasing Activity of a Series of Amphetamines [...].
  4. Heal DJ, Smith SL, Gosden J, Nutt DJ . Amphetamine, past and present--a pharmacological and clinical perspective . Journal of Psychopharmacology . 27 . 6 . 479–496 . June 2013 . 23539642 . 3666194 . 10.1177/0269881113482532 .
  5. Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL . Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter . Drug and Alcohol Dependence . 147 . 1–19 . February 2015 . 25548026 . 4297708 . 10.1016/j.drugalcdep.2014.12.005 . Converging lines of evidence have solidified the notion that DA releasers are substrates of the transporter and once translocated, they reverse the normal direction of transporter flux to evoke release of endogenous neurotransmitters. The nature of this reversal is not well understood, but the entire process is primarily transporter-dependent and requires elevated intracellular sodium concentrations, phosphorylation of DAT, and possible involvement of transporter oligomers (Khoshbouei et al., 2003, 2004; Sitte and Freissmuth, 2010). .
  6. Rothman RB, Blough BE, Baumann MH . Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions . The AAPS Journal . 9 . 1 . E1-10 . January 2007 . 17408232 . 2751297 . 10.1208/aapsj0901001 .
  7. Book: Brust JC . Neurological Aspects of Substance Abuse. 2004. Butterworth-Heinemann. 978-0-7506-7313-6. 117–.
  8. Book: Competitive problems in the drug industry: hearings before Subcommittee on Monopoly and Anticompetitive Activities of the Select Committee on Small Business, United States Senate, Ninetieth Congress, first session . 1976 . U.S. Government Printing Office. 2–.
  9. Parrott AC, Stuart M . Ecstasy (MDMA), amphetamine, and LSD: comparative mood profiles in recreational polydrug users. Human Psychopharmacology: Clinical and Experimental. 1 September 1997. 12. 5. 501–504. 10.1002/(sici)1099-1077(199709/10)12:5<501::aid-hup913>3.3.co;2-m. en. 1099-1077. 10.1.1.515.2896.
  10. Scorza C, Silveira R, Nichols DE, Reyes-Parada M . Effects of 5-HT-releasing agents on the extracellullar hippocampal 5-HT of rats. Implications for the development of novel antidepressants with a short onset of action . Neuropharmacology . 38 . 7 . 1055–1061 . July 1999 . 10428424 . 10.1016/s0028-3908(99)00023-4 .
  11. Morean ME, de Wit H, King AC, Sofuoglu M, Rueger SY, O'Malley SS . The drug effects questionnaire: psychometric support across three drug types . Psychopharmacology . 227 . 1 . 177–192 . May 2013 . 23271193 . 3624068 . 10.1007/s00213-012-2954-z .
  12. Nelson RA, Boyd SJ, Ziegelstein RC, Herning R, Cadet JL, Henningfield JE, Schuster CR, Contoreggi C, Gorelick DA . Effect of rate of administration on subjective and physiological effects of intravenous cocaine in humans . Drug and Alcohol Dependence . 82 . 1 . 19–24 . March 2006 . 16144747 . 10.1016/j.drugalcdep.2005.08.004 .
  13. Berlin I, Warot D, Aymard G, Acquaviva E, Legrand M, Labarthe B, Peyron I, Diquet B, Lechat P . Pharmacodynamics and pharmacokinetics of single nasal (5 mg and 10 mg) and oral (50 mg) doses of ephedrine in healthy subjects . European Journal of Clinical Pharmacology . 57 . 6–7 . 447–455 . September 2001 . 11699608 . 10.1007/s002280100317 . 12410591 .
  14. Powers ME . Ephedra and its application to sport performance: another concern for the athletic trainer? . Journal of Athletic Training . 36 . 4 . 420–424 . October 2001 . 16558668 . 155439 .
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  16. Roelands B, Meeusen R . Alterations in central fatigue by pharmacological manipulations of neurotransmitters in normal and high ambient temperature . Sports Medicine . 40 . 3 . 229–246 . March 2010 . 20199121 . 10.2165/11533670-000000000-00000 . 25717280 .
  17. Miller GM . The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity . Journal of Neurochemistry . 116 . 2 . 164–176 . January 2011 . 21073468 . 3005101 . 10.1111/j.1471-4159.2010.07109.x .
  18. Book: Wu R, Liu J, Li JX . Behavioral Pharmacology of Drug Abuse: Current Status . Trace amine-associated receptor 1 and drug abuse . Adv Pharmacol . 93 . 373–401 . 2022 . 35341572 . 9826737 . 10.1016/bs.apha.2021.10.005 . 978-0-323-91526-7 . It is reported that methamphetamine (METH) interacts with TAAR1 and subsequently inhibits DA uptake, enhance DA efflux and induces DAT internalization, and these effects are dependent on TAAR1 (Xie & Miller, 2009). For example, METH-induced inhibition of DA uptake was observed in TAAR1 and DAT cotransfected cells and WT mouse and monkey striatal synaptosomes but not in DAT-only transfected cells or in striatal synaptosomes of TAAR1-KO mice (Xie & Miller, 2009). TAAR1 activation was enhanced by co-expression of monoamine transporters and this effect could be blocked by monoamine transporter antagonists (Xie & Miller, 2007; Xie et al., 2007). Furthermore, DA activation of TAAR1 induced C-FOS-luciferase expression only in the presence of DAT (Xie et al., 2007)..
  19. Xie Z, Miller GM . A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain . The Journal of Pharmacology and Experimental Therapeutics . 330 . 1 . 316–325 . July 2009 . 19364908 . 2700171 . 10.1124/jpet.109.153775 .
  20. Lewin AH, Miller GM, Gilmour B . Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class . Bioorganic & Medicinal Chemistry . 19 . 23 . 7044–7048 . December 2011 . 22037049 . 3236098 . 10.1016/j.bmc.2011.10.007 . While our data suggest a role for TAAR1 in eliciting amphetamine-like stimulant effects, it must be borne in mind that the observed in vivo effects are likely to result from interaction with both TAAR1 and monoamine transporters. Thus it has been shown that the selective TAAR1 agonist RO5166017 fully prevented psychostimulant-induced and persistent hyperdopaminergia-related hyperactivity in mice.42 This effect was found to be DAT-independent, since suppression of hyperactivity was observed in DAT-KO mice.42 The collected information leads us to conclude that TAAR1 is a stereoselective binding site for amphetamine and that TAAR1 activation by amphetamine and its congeners may contribute to the stimulant properties of this class of compounds. .
  21. Book: Espinoza S, Gainetdinov RR . Taste and Smell . Neuronal Functions and Emerging Pharmacology of TAAR1 . Topics in Medicinal Chemistry . Springer International Publishing . Cham . 23 . 2014 . 978-3-319-48925-4 . 10.1007/7355_2014_78 . 175–194.
  22. Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, Bettler B, Wettstein JG, Borroni E, Moreau JL, Hoener MC . Trace amine-associated receptor 1 modulates dopaminergic activity . The Journal of Pharmacology and Experimental Therapeutics . 324 . 3 . 948–956 . March 2008 . 18083911 . 10.1124/jpet.107.132647 .
  23. Achat-Mendes C, Lynch LJ, Sullivan KA, Vallender EJ, Miller GM . Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1 . Pharmacology, Biochemistry, and Behavior . 101 . 2 . 201–207 . April 2012 . 22079347 . 3288391 . 10.1016/j.pbb.2011.10.025 .
  24. Liu J, Wu R, Li JX . TAAR1 and Psychostimulant Addiction . Cellular and Molecular Neurobiology . 40 . 2 . 229–238 . March 2020 . 31974906 . 7845786 . 10.1007/s10571-020-00792-8 .
  25. Kuropka P, Zawadzki M, Szpot P . A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse . Hum Psychopharmacol . 38 . 3 . e2866 . May 2023 . 36866677 . 10.1002/hup.2866 . Another feature that distinguishes [substituted cathinones (SCs)] from amphetamines is their negligible interaction with the trace amine associated receptor 1 (TAAR1). Activation of this receptor reduces the activity of dopaminergic neurones, thereby reducing psychostimulatory effects and addictive potential (Miller, 2011; Simmler et al., 2016). Amphetamines are potent agonists of this receptor, making them likely to self‐inhibit their stimulating effects. In contrast, SCs show negligible activity towards TAAR1 (Kolaczynska et al., 2021; Rickli et al., 2015; Simmler et al., 2014, 2016). [...] The lack of self‐regulation by TAAR1 may partly explain the higher addictive potential of SCs compared to amphetamines (Miller, 2011; Simmler et al., 2013)..
  26. Simmler LD, Liechti ME . Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances . Handb Exp Pharmacol . 252 . 143–164 . 2018 . 29633178 . 10.1007/164_2018_113 . The activation of human TAAR1 might diminish the effects of psychostimulation and intoxication arising from 7-APB effects on monoamine transporters (see 4.1.3. for more details). Affinity to mouse and rat TAAR1 has been shown for many psychostimulants, but species differences are common (Simmler et al. 2016). For example, [5-(2-aminopropyl)indole (5-IT)] and [4-methylamphetamine (4-MA)] bind and activate TAAR1 in the nanomolar range, but do not activate human TAAR1..
  27. Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME . In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1 . J Pharmacol Exp Ther . 357 . 1 . 134–144 . April 2016 . 26791601 . 10.1124/jpet.115.229765 .
  28. Rickli A, Kolaczynska K, Hoener MC, Liechti ME . Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR . Neurotoxicology . 72 . 95–100 . May 2019 . 30776375 . 10.1016/j.neuro.2019.02.011 . 2019NeuTx..72...95R .
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  30. Schmitt KC, Rothman RB, Reith ME . Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates . The Journal of Pharmacology and Experimental Therapeutics . 346 . 1 . 2–10 . July 2013 . 23568856 . 3684841 . 10.1124/jpet.111.191056 .
  31. Schmitt KC, Reith ME . The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors . PLOS ONE . 6 . 10 . e25790 . 2011 . 22043293 . 3197159 . 10.1371/journal.pone.0025790 . free . 2011PLoSO...625790S .
  32. Tanda G, Hersey M, Hempel B, Xi ZX, Newman AH . Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder . Current Opinion in Pharmacology . 56 . 13–21 . February 2021 . 32927246 . 8247144 . 10.1016/j.coph.2020.07.007 .
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  47. Moratalla R, Khairnar A, Simola N, Granado N, García-Montes JR, Porceddu PF, Tizabi Y, Costa G, Morelli M . Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms . Prog Neurobiol . 155 . 149–170 . August 2017 . 26455459 . 10.1016/j.pneurobio.2015.09.011 . 10261/156486 . free .
  48. Baumeister AA . Is Attention-Deficit/Hyperactivity Disorder a Risk Syndrome for Parkinson's Disease? . Harv Rev Psychiatry . 29 . 2 . 142–158 . 2021 . 33560690 . 10.1097/HRP.0000000000000283 . It has been suggested that the association between PD and ADHD may be explained, in part, by toxic effects of these drugs on DA neurons.241 [...] An important question is whether amphetamines, as they are used clinically to treat ADHD, are toxic to DA neurons. In most of the animal and human studies cited above, stimulant exposure levels are high relative to clinical doses, and dosing regimens (as stimulants) rarely mimic the manner in which these drugs are used clinically. The study by Ricaurte and colleagues248 is an exception. In that study, baboons orally self-administered a racemic (3:1 d/l) amphetamine mixture twice daily in increasing doses ranging from 2.5 to 20 mg/day for four weeks. Plasma amphetamine concentrations, measured at one-week intervals, were comparable to those observed in children taking amphetamine for ADHD. Two to four weeks after cessation of amphetamine treatment, multiple markers of striatal DA function were decreased, including DA and DAT. In another group of animals (squirrel monkeys), d/l amphetamine blood concentration was titrated to clinically comparable levels for four weeks by administering varying doses of amphetamine by orogastric gavage. These animals also had decreased markers of striatal DA function assessed two weeks after cessation of amphetamine..
  49. Asser A, Taba P . Psychostimulants and movement disorders . Front Neurol . 6 . 75 . 2015 . 25941511 . 4403511 . 10.3389/fneur.2015.00075 . free . Amphetamine treatment similar to that used for ADHD has been demonstrated to produce brain dopaminergic neurotoxicity in primates, causing the damage of dopaminergic nerve endings in the striatum that may also occur in other disorders with long-term amphetamine treatment (57)..
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  52. Ricaurte GA, Mechan AO, Yuan J, Hatzidimitriou G, Xie T, Mayne AH, McCann UD . Amphetamine treatment similar to that used in the treatment of adult attention-deficit/hyperactivity disorder damages dopaminergic nerve endings in the striatum of adult nonhuman primates . J Pharmacol Exp Ther . 315 . 1 . 91–98 . October 2005 . 16014752 . 10.1124/jpet.105.087916 .
  53. Courtney KE, Ray LA . Clinical neuroscience of amphetamine-type stimulants: From basic science to treatment development . Prog Brain Res . 223 . 295–310 . 2016 . 26806782 . 10.1016/bs.pbr.2015.07.010 . Repeated exposure to moderate to high levels of methamphetamine has been related to neurotoxic effects on the dopaminergic and serotonergic systems, leading to potentially irreversible loss of nerve terminals and/or neuron cell bodies (Cho and Melega, 2002). Preclinical evidence suggests that d-amphetamine, even when administered at commonly prescribed therapeutic doses, also results in toxicity to brain dopaminergic axon terminals (Ricaurte et al., 2005)..
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  61. Web site: Baggott M . [Comment] ]. 21 January 2022 . I measured DA and 5-HT release in vitro and [2-FMA] basically didn't release 5-HT (EC50s were around 90 nM at DAT and 15000 nM at SERT)..
  62. Web site: Baggott M . [Comment] ]. 30 April 2024 . [2-FMA is] a potent substrate-type releaser at NET and DAT (EC50s below 100 nM) but not SERT. [...] It's my own (Tactogen's, really) unpublished data. I assayed it while trying to understand the Borax combo..
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