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] However, there is indication that TAAR1, although non-essential for release, may augment the potency of amphetamines as dopamine releasing agents, at least in vitro . [26]

Generic pharmacophore for MRAs. Substitutions at the nitrogen, a-carbon, or phenyl ring extending beyond the red circle will result in partial releasers, transporter blockers, or be inactive. Monoamine releasing agent pharmacophore.png
Generic pharmacophore for MRAs. Substitutions at the nitrogen, α-carbon, or phenyl ring extending beyond the red circle will result in partial releasers, transporter blockers, or be inactive.

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 induce 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]

Chemical families

Monoamine releasing agents are usually arylalkylamines. A number of different structural families of compounds have been found to act as MRAs. The possible structural forms of monoamine releasing agents 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

Amine fused into ring

Alkyl chain fused into ring

Tryptamine-like

Ring-less (alkylamines)

Chemical family structure examples of monoamine releasing agents

Activity 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] [100] [3] [5] [101] 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] [100] [3] [101] These researchers developed an assay measuring monoamine release from rat brain synaptosomes in 1999 that has subsequently been widely employed. [101] [100] [40] [102] [103] 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. [104] [5] [101]

Activity profiles of monoamine releasing agents in rat brain synaptosomes (EC50 Tooltip half-maximal effective concentration, nM) [2] [3] [4]
CompoundPAL # 5-HT Tooltip Serotonin NE Tooltip Norepinephrine DA Tooltip DopamineTypeClassRef
1-Methyl-T PAL-63753.1>10000>10000SRATryptamine [11]
1-Phenylpiperazine (PP)ND8801862530SNRAPhenylpiperazine [81]
2-Aminoindane (2-AI, AI)ND>1000086439NDRAAminoindane [82]
2-APBT ND8.921.638.6SNDRAAPBT [69]
2-BMC ND2837156650NDRACathinone [105]
2-CA NDND19.162.4NDAmphetamine [4]
2-CMC ND281593179NDRACathinone [105]
2-FA NDND24.138.1NDAmphetamine [4]
2-FMA ND~15000<100~90NDRAAmphetamine [106] [107]
2-FMC ND>10000ND
(85% at 10 μM)		48.7NDRACathinone [88]
2-FPM ND480828112NDRAPhenylmorpholine [108]
2-MA NDND37127NDAmphetamine [4]
2-MeO-A NDND4731478NDAmphetamine [4]
2-MeO-MC ND7220339920NDRACathinone [105]
2-MMC ND347–4905381–97.9SNDRACathinone [88] [105]
2-MPM ND1758102374NDRAPhenylmorpholine [109]
2-Phenylmorpholine PAL-63220260
(31% at 10 μM)		79
(96% at 10 μM)		86
(98% at 10 μM)		NDRAPhenylmorpholine [110]
2-TFMeO-MC ND>10000ND
(33% at 10 μM)		>10000IACathinone [88]
2-TFMMC (2-TFMAP)ND8400–>100002200
(69% at 10 μM)		8000–>10000SNDRACathinone [111] [88] [112] [105]
2C-C ND>100000>100000100000IAPhenethylamine [61] [113]
2C-D NDIAIAIAIAPhenethylamine [113]
2C-E ND>100000>100000>100000IAPhenethylamine [61] [113]
2C-I ND>100000>100000>100000IAPhenethylamine [61] [113]
2C-T-2 NDIAIAIAIAPhenethylamine [113]
3-APBT ND21.913.421.7SNDRAAPBT [69]
3-BCPC PAL-586621NDIA (RI)NDCathinone [104]
3-BMC ND136–1372521–28.0SNDRACathinone [88] [114] [105]
3-CA PAL-3041209.411.8SNDRAAmphetamine [76] [4] [104] [104] [115]
3-CC ND56710564SNDRACathinone [116] [114]
3-CCPC (RTI-6037-39)PAL-4331328NDIA (RI)NDCathinone [104] [117]
  (–)-3-CCPCPAL-1122562NDIA (RI)NDCathinone [104]
  (+)-3-CCPCPAL-1123733NDIA (RI)NDCathinone [104]
3-CEC PAL-361IANDIANDCathinone [104]
3-Cl-4-Me-CPC PAL-820181NDIA (RI)NDCathinone [104]
3′-Cl-5-Me-PM PAL-738236558SNDRAPhenylmorpholine [73] [118]
3-CMC (clophedrone)PAL-434211–41019–54.426–46.8SNDRACathinone [5] [88] [114] [105] [104] [119] [104]
3-CPC PAL-363IANDIA (RI)NDCathinone [104]
3′-CPM PAL-59430175
(82% at 10 μM)		27
(100% at 10 μM)		NDPhenylmorpholine [118] [110]
3-FA PAL-353193716.124.2NDRAAmphetamine [120] [4]
3-FMC ND1460ND
(100% at 10 μM)		64.8NDRACathinone [88]
3′-FPM PAL-5931269–255817–3043–60NDRAPhenylmorpholine [108] [110]
3-MA PAL-31421818.333.3NDRAAmphetamine [120] [76] [4]
3-MCPC PAL-5881067NDIA (RI)NDCathinone [104]
3-MeO-A NDND58.0103NDAmphetamine [4]
3-MeO-CPC PAL-5911014NDIA (RI)NDCathinone [104]
3-MeO-MC ND306–683111
(68% at 10 μM)		109–129SNDRACathinone [88] [114] [105]
3-MeO-PM PAL-823ND
(78% at 10 μM)		ND
(86% at 10 μM)		ND
(96% at 10 μM)		NDPhenylmorpholine [110]
3-MMC ND268–2922728–70.6SNDRACathinone [5] [88] [114] [105]
3-MPM PAL-7738662227SNDRAPhenylmorpholine [109]
3-TFMeO-MC ND188ND
(79% at 10 μM)		729SNDRACathinone [88]
3-TFMMC (3-TFMAP)ND297–3802700
(78% at 10 μM)		610–1290SNDRACathinone [111] [88] [112] [105]
3,4-DCCPC PAL-787356NDIA (RI)NDCathinone [104]
4-APBT ND21.246.266.6SNDRAAPBT [69]
4-Benzylpiperidine ND524641.4109NDRABenzylpiperidine [121]
4-BMC (brephedrone)ND42.5–60.210059.4SNDRACathinone [122] [88] [114] [105] [123] [124]
4-CA (PCA)ND28.323.5–26.242.2–68.5SNDRAAmphetamine [76] [4] [125] [126]
4-CC ND128.485.1221.8SNDRACathinone [125]
4-CCPC PAL-7431632NDIA (RI)NDCathinone [104]
4-CEA (PCEA)ND33.8162.6238.0SNDRAAmphetamine [125] [126]
4-CEC ND152.65194.0353.6SDRACathinone [125]
4-CMA (PCMA)ND29.936.554.7SNDRAAmphetamine [125] [126]
4-CMC (clephedrone)ND71.1–14444–90.942.2–74.7SNDRACathinone [122] [88] [125] [114] [105] [123] [124]
4-Et-PEA PAL-505NDND2087NDPhenethylamine [5]
4-FA PAL-303730–93928.0–3751.5–200NDRAAmphetamine [120] [61] [76] [4]
4-Fluoro-T PAL-5511081123106SDRATryptamine [11]
4-FMC (flephedrone)ND1290–14506283.4–119NDRACathinone [122] [88] [114] [123] [124]
4-FPM PAL-6352403
(88% at 10 μM)		285
(100% at 10 μM)		529
(95% at 10 μM)		SNDRAPhenylmorpholine [110]
4′-FPM PAL-748189558191NDRAPhenylmorpholine [108] [110]
4-iPr-PEA PAL-595NDNDIANDPhenethylamine [5]
4-MA PAL-31353.422.244.1SNDRAAmphetamine [120] [76] [4]
4-MAR NDNDNDNDNDPhenyloxazolamine [127]
  cis-4-MARND53.24.81.7NDRAPhenyloxazolamine [127] [128]
4-MBA NDIAIAIAIAAmphetamine [129]
4-MCPC PAL-744667NDIA (RI)NDCathinone [104]
4-MEA ND102182550SNDRAAmphetamine [129]
4-MeO-MC (methedrone)ND120–195111506–881SNDRACathinone [122] [88] [114] [105] [123] [124]
4-MeO-T PAL-5484114>10000>10000SRATryptamine [11]
4-MMA ND67.466.941.3SNDRAAmphetamine [129] [123]
4-MPA ND650752IASNRAAmphetamine [129]
4-MPEA (4-Me-PEA)PAL-503NDND271NDPhenethylamine [5]
4-MPM PAL-7478662227SNDRAPhenylmorpholine [109] [110]
4-MTA NDNDNDNDSNDRAAmphetamine [130] [131] [132]
4-MTMA PAL-106321NDNDSNDRAAmphetamine [73]
4-tBu-MC NDIAND942
(Emax Tooltip maximal efficacy ≈ 50%)		NDCathinone [133]
4-TFMeO-MC ND118ND7510NDCathinone [88]
4-TFMMC (4-TFMAP)ND190–2709002700–4230SNRACathinone [134] [122] [111] [112] [124] [105]
4,4'-DMAR NDNDNDNDSNDRAPhenyloxazolamineND
  cis-4,4'-DMARND17.7–59.911.8–31.68.6–24.4SNDRAPhenyloxazolamine [128] [135] [127]
  trans-4,4'-DMARND59.931.624.4SNDRAPhenyloxazolamine [135] [127]
5-APB ND192131SNDRAAmphetamine [65]
5-APBT ND10.338.492.8SNDRAAPBT [69]
5-API (5-IT)PAL-57128–104.813.3–7912.9–173SNDRAAmphetamine [12] [71]
5-Bromo-T PAL-51875.0>10000478SDRATryptamine [11]
5-Chloro-αET PAL-52633.2>10000IA (RI)SRAα-Ethyltryptamine [11]
5-Chloro-αMT PAL-54216.2343454.3SDRAα-Methyltryptamine [11] [12]
5-Chloro-T PAL-44119.1>10000476SRATryptamine [11]
5-Fluoro-αET PAL-54536.65334150SDRAα-Ethyltryptamine [11]
5-Fluoro-αMT PAL-544
PAL-212		14–1978–12632–37SNDRAα-Methyltryptamine [12] [11] [41]
5-Fluoro-T PAL-28410.146482.3SDRATryptamine [11]
5-MABB (5-MBPB)NDNDNDNDNDAmphetamine [68] [136]
  (S)-5-MABBND31158210SNDRAAmphetamine [68] [136]
  (R)-5-MABBND49850IASRAAmphetamine [68] [136]
5-MAPB ND64–902441–459SNDRAAmphetamine [65] [137]
  (S)-5-MAPBND67ND258NDAmphetamine [137]
  (R)-5-MAPBND184ND1951NDAmphetamine [137]
5-MeO-αMT ND46089001500SNDRAα-Methyltryptamine [61]
5-MeO-DALT ND>100000>100000>100000IATryptamine [61]
5-MeO-DET NDIA (RI)IAIASRITryptamine [41]
5-MeO-DiPT ND>100000 (RI)>100000 (RI)>100000IATryptamine [61] [41]
5-MeO-DMT ND>100000 (RI)>100000 (RI)>100000IATryptamine [61] [41]
5-MeO-DPT NDIA (RI)IAIA (RI)SRITryptamine [41]
5-MeO-MiPT ND>100000>100000>100000IATryptamine [61] [41]
5-MeO-NET ND284>10000>10000SRATryptamine [41]
5-MeO-NiPT NDIA (RI)IAIASRITryptamine [41]
5-MeO-NMT ND1114>10000>10000SRATryptamine [41]
5-MeO-T PAL-2342169>1000011031SDRATryptamine [11] [41]
5-Methyl-T PAL-22139>10000>10000SRATryptamine [11]
6-APB ND361410SNDRAAmphetamine [65]
6-APBT ND10.713.67.2SNDRAAPBT [69]
6-API (6-IT)ND19.925.6164.0SNDRAAmphetamine [71]
6-Fluoro-T PAL-2274.41575106SRATryptamine [11]
6-MABB (6-MBPB)NDNDNDNDNDAmphetamine [68] [136]
  (R)-6-MABBND172227IASNRAAmphetamine [68] [136]
  (S)-6-MABBND547741SNDRAAmphetamine [68] [136]
6-MAPB ND331420SNDRAAmphetamine [65]
6-MeO-T PAL-26353.8465113SNDRATryptamine [11]
6-Methyl-T PAL-52251.6>10000353SDRATryptamine [11]
7-APBT ND36.928.516.8SNDRAAPBT [69]
7-Chloro-T PAL-5328.036561330SRATryptamine [11]
7-MeO-T PAL-53344.656002118SRATryptamine [11]
7-Methyl-T PAL-28623.7>100003380SRATryptamine [11]
α-Ethyltryptamine (AET, αET)PAL-12523.2640232SDRAα-Ethyltryptamine [11]
  (–)-α-EthyltryptaminePAL-64054.93670654SRAα-Ethyltryptamine [11]
  (+)-α-EthyltryptaminePAL-64734.759257.6SDRAα-Ethyltryptamine [11]
α-Me-MC (βk-mephentermine; RAD-081)ND12860153590NDRACathinone [138] [139] [140]
α-Methylisotryptamine (isoAMT)PAL-569177811062SNRAIsotryptamine [12]
α-Methyltryptamine (αMT; AMT)PAL-1721.7–6879–11278.6–180SNDRAα-Methyltryptamine [61] [11] [141]
βk-NMPEA (FTS-096)ND>600001481860NRAPhenethylamine [138] [139] [140]
AMAPN ND21ND55NDCathinone [88] [142]
Amfepramone (diethylpropion)ND>10000>10000>10000PDCathinone [143] [103]
Aminorex ND193–41415.1–26.49.1–49.4SNDRAPhenyloxazolamine [40] [128] [4] [127] [103]
Amphetamine (A)NDNDNDNDNDRAAmphetamineND
   Dextroamphetamine ND698–17656.6–10.25.8–24.8NDRAAmphetamine [40] [144] [4] [133] [103]
   Levoamphetamine NDND9.527.7NDRAAmphetamine [76] [4] [145] [146]
APPEA (α-Pr-PEA)PAL-550IANDIA (RI)NDAmphetamine [5] [104]
BDB ND1805402,300NDRAAmphetamine [61]
Benzylpiperazine (BZP)ND6050–>1000062–68175–600NDRAPhenylpiperazine [61] [147] [3] [4] [148]
BK-NM-AMT ND41.3ND
(55% at 10 μM)		92.8SDRAα-Methyltryptamine [88] [142] [89]
BK-5F-NM-AMT ND190ND620NDα-Methyltryptamine [149]
BK-5Cl-NM-AMT ND200ND865NDα-Methyltryptamine [149]
BK-5Br-NM-AMT ND295ND2100NDα-Methyltryptamine [149]
BMAPN ND27ND34NDCathinone [88] [142]
BMPEA (β-Me-PEA)NDND126627NDPhenethylamine [150]
Bufotenin (DMS, 5-HO-DMT)ND30.5>10000>10000SRATryptamine [41]
Buphedrone (βk-MEPEA)PAL-429IAND411NDCathinone [104]
Bupropion (amfebutamone)NDIA (RI)IA (RI)IA (RI)NDRICathinone [140] [116] [114]
Butylamphetamine (NBA, BA)PAL-90NDNDIANDAmphetamine [5]
Butylone (βk-MBDB)ND330IA (RI)IA (RI)SRA/NDRICathinone [151] [152]
Cathinone (C; βk-AMPH)ND6100–759523.6–25.634.8–83.1NDRACathinone [4] [88] [125]
  D-CathinoneND>1000072.0183.9NDRACathinone [153]
  L-CathinoneND2366–926712.4–2818–24.6NDRACathinone [154] [116] [153]
Chlorphentermine ND18.2–30.9>10000 (RI)935–2650SRAAmphetamine [40] [103]
DEPEA (α-Et-EPEA)NDND209604NDAmphetamine [155]
Dibutylone NDIAIA (RI)IA (RI)DRICathinone [156]
Diethyltryptamine (DET)NDIA (RI)IAIASRITryptamine [41]
Diisopropyltryptamine (DiPT)NDIA (RI)IA (RI)IASRITryptamine [41]
Dimethylamphetamine NDND2231250NDAmphetamine [150]
Dimethyltryptamine (DMT)ND1144166>10000SRATryptamine [41]
Dipropyltryptamine (DPT)ND>100000 (RI)>100000 (RI)>100000 (RI)IATryptamine [61] [41]
DMPP (2,3-DMPP)PAL-21824–2613.7–561207–1320SNRAPhenylpiperazine [73] [81]
DOC NDIAIAIAIAAmphetamine [113]
Dopamine (DA)ND>10000 (RI)66.286.9NDRAPhenethylamine [40] [4]
EDMA ND117325597SNDRAAmphetamine [62] [123]
EDMC ND347327496SNDRACathinone [62] [123]
ENAP PAL-10451213746SDRAAmphetamine [73]
Ephedrine (racephedrine)NDNDNDNDNDRACathinolND
   D-Ephedrine (ephedrine)ND>1000043.1–72.4236–1350NDRACathinol [40] [4]
  L-EphedrineND>100002182104NRACathinol [40] [154]
Ephylone NDIA (RI)IA (RI)IA (RI)IA (NDRI)Cathinone [157]
Epinephrine NDNDNDNDNDRAPhenethylamineND
Ethcathinone (EC)ND1923–211888.3–99.3267.6–>1000NRACathinone [143] [4] [125] [133]
Ethylamphetamine (EA)PAL-99NDND88.5NDAmphetamine [5]
  S(+)-EthylamphetamineND333.028.844.1NDRAAmphetamine [125] [126]
Ethylone (βk-MDEA)ND617.442511122SNDRACathinone [123]
Eutylone (βk-EBDB)ND1020IA (RI)IA (RI)SRA/NDRICathinone [156]
Fenfluramine (3-TFM-EA)ND79.3–108739>10000 (RI)SRAAmphetamine [40] [158] [159] [4]
   D-Fenfluramine ND51.7302>10000SNRAAmphetamine [40] [158]
   L-Fenfluramine ND147>10000>10000SRAAmphetamine [158] [160]
HHA NDND333485NDAmphetamine [4]
HHMA ND172977130NDRAAmphetamine [4] [161]
HHMC ND1410011090NDRACathinone [162]
HMA ND8976941450–3423SNDRAAmphetamine [4] [163] [164]
HMMA ND589–607625607–3652SNDRAAmphetamine [4] [163] [164] [161]
HMMC ND721063405840SNDRACathinone [162]
MBDB ND5403300>100000SNRAAmphetamine [61]
mCPP (3-CPP, 3CPP)ND28–38.1≥140063000SRAPhenylpiperazine [61] [160] [165]
MDA ND160–16247–108106–190SNDRAAmphetamine [159] [4] [65]
  (R)-MDAND310290900SNDRAAmphetamine [159] [4]
  (S)-MDAND10050.098.5SNDRAAmphetamine [159] [4]
MDAI ND1141171334SNRAAminoindane [82]
MDC ND966394370SNDRACathinone [162]
MDEA PAL-192472608622SNDRAAmphetamine [73]
  (R)-MDEAPAL-19352651507SNDRAAmphetamine [73]
  (S)-MDEAPAL-194465RIRISRAAmphetamine [73]
MDMA ND50–8554–11051–278SNDRAAmphetamine [40] [166] [71] [159] [4] [65]
   (R)-MDMA ND3405603700SNDRAAmphetamine [159] [4]
  (S)-MDMAND74136142SNDRAAmphetamine [159] [4]
MDMAR NDNDNDNDSNDRAPhenyloxazolamineND
  cis-MDMARND43.914.810.2SNDRAPhenyloxazolamine [135]
  trans-MDMARND73.438.936.2SNDRAPhenyloxazolamine [135]
MDPV NDIA13
(Emax Tooltip maximal efficacy = 24%)		2.3
(Emax = 24%)		NDRIPhenylethylpyrrolidine [144] [123]
MEAI (5-MeO-AI)ND1348612646SNRAAminoindane [82]
MEPEA (α-Et-MPEA)PAL-426469858179–225SNDRAAmphetamine [104] [155]
Mephedrone (4-MMC)ND118.3–12258–62.749.1–51SNDRACathinone [166] [144] [88] [105] [124]
  S(–)-MephedroneND61ND74NDCathinone [133] [167]
  R(+)-MephedroneND1470ND31NDCathinone [133] [167]
Mesocarb NDNDND>100000 (RI)DRIAmphetamine [168]
Methamphetamine (MA)NDNDNDNDNDRAAmphetamineND
   Dextromethamphetamine ND736–129212.3–14.38.5–40.4NDRAAmphetamine [40] [166] [4] [103]
   Levomethamphetamine ND464028.5416NRAAmphetamine [40] [4]
Methcathinone (MC)ND2592–585322–26.112.5–49.9NDRACathinone [4] [88] [114] [105] [125]
  D-MethcathinoneNDIANDNDNRACathinone [140]
  L-MethcathinoneND177213.114.8NDRACathinone [154] [133]
Methiopropamine NDIA (RI)IA (RI)IA (RI)NDRIThiopropamine [169] [170]
Methylone (MDMC)ND234–708140–270117–220SNDRACathinone [166] [144] [123] [156] [162]
Methylphenidate NDIA (RI)IA (RI)IA (RI)NDRIPhenidate [3] [94] [171]
Mexedrone (4-MMC-MeO)ND2525IA (RI)IA (RI)SRA/NDRICathinone [172]
MiPT NDIAIAIAIATryptamine [41]
MMAI ND313101>10000SRAAminoindane [82]
MNAP (methamnetamine)PAL-1046133410SNDRAAmphetamine [73] [5]
MPPA (BMMPEA, β-Me-NMPEA)NDND154574NDPhenethylamine [150]
Naphthylisopropylamine (NAP)PAL-2873.411.112.6SNDRAAmphetamine [173] [4]
Naphthylmetrazine PAL-704IA (RI203111NDRA/SRIPhenylmorpholine [110]
Naphthylmorpholine PAL-678ND
(92% at 10 μM)		ND
(88% at 10 μM)		ND
(79% at 10 μM)		NDPhenylmorpholine [110]
NET (NETP; N-Et-T)PAL-53618.6IA (RI)IA (RI)SRATryptamine [11] [41]
NiPT NDIA (RI)IAIASRITryptamine [41]
NMT PAL-15222.4733321SRATryptamine [11] [41]
Norephedrine (phenylpropanolamine)NDNDNDNDNDRACathinolND
  D-NorephedrineND>1000042.1302NDRACathinol [154]
  L-NorephedrineND>100001371371NRACathinol [154]
Norepinephrine (NE)ND>10000164869NDRAPhenethylamine [40] [4]
Norfenfluramine (3-TFMA)ND104168–1701900–1925SNRAAmphetamine [158] [159]
  (+)-NorfenfluramineND59.372.7924SNRAAmphetamine [158]
  (–)-NorfenfluramineND287474>10000SNRAAmphetamine [158]
Normephedrone (4-MC)ND210100220SNDRACathinone [174] [153] [133]
  R(+)-NormephedroneND17989150SNDRACathinone [133] [153]
  S(–)-NormephedroneND1592115391NDRACathinone [133] [153]
Norpropylhexedrine NDNDNDNDNDRACyclohexylethylamineND
Norpseudoephedrine NDNDNDNDNDRACathinolND
   D-Norpseudoephedrine (cathine)ND>1000015.068.3NDRACathinol [154]
   L-Norpseudoephedrine ND>1000030.1294NDRACathinol [154]
ODMA NDNDNDNDSNDRAAmphetamine [75]
oMPP (2-MPP)PAL-16917539.1296–542SNDRAPhenylpiperazine [175] [5] [81]
PMA (4-MeO-A)NDND166867SNDRAAmphetamine [4] [87] [132]
PMMA (4-MeO-MA)NDNDNDNDSNDRAAmphetamine [132]
  (S)-PMMAND411471000SNRAAmphetamine [134] [176] [87]
  (R)-PMMAND134>140001600SRAAmphetamine [134] [176] [87]
Pentylone ND476–1030
(Emax Tooltip maximal efficacy ≈ 50%)		IA (RI)IA (RI)SRA/NDRICathinone [151] [156] [157]
Phenacylamine (βk-PEA)PAL-27>10000ND
(96% at 10 μM)		208NDRAPhenethylamine [5] [88] [133]
Phendimetrazine ND>100000>10000>10000PDPhenylmorpholine [177] [4] [103]
Phenethylamine (PEA)ND>1000010.939.5NDRAPhenethylamine [5] [76] [4]
Phenmetrazine (PM)PAL-557765–>1000029–50.470–131NDRAPhenylmorpholine [177] [4] [109] [110]
Phentermine (P, PH)ND2575–351128.8–39.4262NDRAAmphetamine [40] [4] [103]
Phenylalaninol NDNDNDNDNDAmphetamineND
  D-PhenylalaninolPAL-329>100001061355NRAAmphetamine [175]
Phenylbutenamine NDNDNDNDNDPhenylbutenamineND
  (3E)-PhenylbutenaminePAL-881>10000308666SNRAPhenylbutenamine [77] [78]
  (3Z)-PhenylbutenaminePAL-893>100003011114SNRAPhenylbutenamine [77] [78]
Phenylbutynamine PAL-874>10000305688NDRAPhenylbutynamine [73]
Phenylisobutylamine (α-Et-PEA, AEPEA)PAL-426469880225–273NDRAAmphetamine [5] [104] [115] [155]
Phenylpropylamine NDND2221491NDRAPhenylpropylamine [76] [4]
pMeOPP (4-MeOPP)ND3200440–15006300–11000SNRAPhenylpiperazine [61] [81]
pMPP (4-MPP)PAL-233NDNDIA (RI)NDPhenylpiperazine [5]
pNPP (4-NPP)PAL-17519–43
(Emax Tooltip maximal efficacy = 57%)		>10000>10000SRAPhenylpiperazine [73] [81]
Propylamphetamine (PA)PAL-424NDNDRI (1013)NDAmphetamine [5]
Propylcathinone (PC)PAL-359NDNDIANDCathinone [5] [133]
Propylhexedrine NDNDNDNDNDRACyclohexylethylamineND
Propylone ND3128IA (RI)975.9SDRACathinone [123]
Pseudoephedrine (racemic)NDNDNDNDNDRACathinolND
   D-Pseudoephedrine ND>1000040929125NDRACathinol [154]
   L-Pseudoephedrine (pseudoephedrine)ND>100002241988NRACathinol [154]
Pseudophenmetrazine ND>10000514RINRAPhenylmorpholine [177]
Psilocin PAL-153561
(Emax Tooltip maximal efficacy = 54%)		>10000>10000SRATryptamine [73] [41]
SeDMA NDNDNDNDSNDRAAmphetamine [75]
Serotonin (5-HT)ND44.4>10000 (RI)≥1960SRATryptamine [40] [4]
TDMA NDNDNDNDSNDRAAmphetamine [75]
TFMCPP (3-TFM-4-C-PP)PAL-17933
(Emax Tooltip maximal efficacy = 66%)		>10000>10000SRAPhenylpiperazine [73]
TFMPP (3-TFMPP)ND121>10000>10000SRAPhenylpiperazine [147] [148] [4]
TMA (3,4,5-TMeO-A)ND16000>100000>100000IAAmphetamine [61]
TMA-2 (2,4,5-TMeO-A)ND>100000>100000>100000IAAmphetamine [61]
TMA-6 (2,4,6-TMeO-A)ND>100000>100000>100000IAAmphetamine [61]
Tramadol NDIA (RI)IA (RI)IASNRIND [3]
Tryptamine (T)PAL-23532.6716164SDRATryptamine [41] [11]
Tyramine ND277540.6119NDRAPhenethylamine [40] [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.

Another method of measuring monoamine release involves the use of human HEK293 cells transfected with and expressing monoamine transporters. [178] [179] [59] [127] [62] However, monoamine releasing agents show differing and much lower potencies in this system compared to rat brain synaptosomes, and it is much less frequently employed. [178] [179] [59] [127] [62] 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. [62] [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] [90] The monoamine-releasing activities of phenethylamine are abolished in the brain synaptosomes of TAAR1 knockout mice. [180] Conversely however, while TAAR1 may also be involved in the releasing effects of amphetamines, the TAAR1 is not essential for monoamine release by these agents and other monoamine releasers. [90] [23] [24] [25] [26] [33]

Related Research Articles

<span class="mw-page-title-main">Phenethylamine</span> Organic compound, a stimulant in humans

Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.

<span class="mw-page-title-main">Tryptamine</span> Metabolite of the amino acid tryptophan

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

<span class="mw-page-title-main">3,4-Methylenedioxyamphetamine</span> Empathogen-entactogen, psychostimulant, and psychedelic drug of the amphetamine family

3,4-Methylenedioxyamphetamine (MDA), sometimes referred to as “sass,” is an empathogen-entactogen, stimulant, and psychedelic drug of the amphetamine family that is encountered mainly as a recreational drug. In its pharmacology, MDA is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). In most countries, the drug is a controlled substance and its possession and sale are illegal.

<span class="mw-page-title-main">Dopamine transporter</span> Mammalian protein found in Homo sapiens

The dopamine transporter is a membrane-spanning protein coded for in humans by the SLC6A3 gene, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

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

Naphthylaminopropane, also known as naphthylisopropylamine (NIPA), is an experimental drug that was under investigation for the treatment of alcohol and stimulant addiction.

<span class="mw-page-title-main">5-Fluoro-AMT</span> Chemical compound

5-Fluoro-α-methyltryptamine, also known as PAL-212 or PAL-544, is a putative stimulant, entactogen, and psychedelic tryptamine derivative related to α-methyltryptamine (αMT).

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

Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.

<span class="mw-page-title-main">Norepinephrine releasing agent</span> Catecholaminergic type of drug

A norepinephrine releasing agent (NRA), also known as an adrenergic releasing agent, is a catecholaminergic type of drug that induces the release of norepinephrine (noradrenaline) and epinephrine (adrenaline) from the pre-synaptic neuron into the synapse. This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine therefore an increase in adrenergic neurotransmission.

<span class="mw-page-title-main">Dopamine releasing agent</span> Type of drug

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

<span class="mw-page-title-main">Norepinephrine–dopamine releasing agent</span> Drug class

A norepinephrine–dopamine releasing agent (NDRA) is a type of drug which induces the release of norepinephrine and 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">Phenylpiperazine</span> Chemical compound

1-Phenylpiperazine is a simple chemical compound and drug featuring a phenyl group bound to a piperazine ring. The suffix ‘-piprazole’ is sometimes used in the names of drugs to indicate they belong to this class.

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

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

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

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

Substituted β-hydroxyamphetamines, or simply β-hydroxyamphetamines, also known as phenylisopropanolamines, phenylpropanolamines, norephedrines, or 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">2-Aminoacetophenone</span> Phenethylamine derivative

Phenacylamine, also known as β-ketophenethylamine, α-desmethylcathinone, or 2-aminoacetophenone, is a substituted phenethylamine derivative. It is the phenethylamine homologue of cathinone (β-ketoamphetamine) and hence is a parent compound of a large number of stimulant and entactogen drugs.

<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.

<span class="mw-page-title-main">2-Fluoromethcathinone</span> Designer stimulant

2-Fluoromethcathinone (2-FMC), also known as 2-flephedrone, is a psychostimulant and designer drug of the cathinone family. It acts as a dopamine and norepinephrine releasing agent (NDRA).

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