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A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

Types of MRAs

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

• Selective for one neurotransmitter
  • Serotonin releasing agent (SRA)
  • Norepinephrine releasing agent (NRA)
  • Dopamine releasing agent (DRA)
• Non-selective, releasing two or more neurotransmitters
  • Norepinephrine–dopamine releasing agent (NDRA)
  • Serotonin–norepinephrine releasing agent (SNRA)
  • Serotonin–dopamine releasing agent (SDRA)
  • Serotonin–norepinephrine–dopamine releasing agent (SNDRA)

Mechanism of action

MRAs cause the release of monoamine neurotransmitters by various complex mechanism of actions. They may enter the presynaptic neuron primarily via plasma membrane transporters, such as the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT). Some, such as exogenous phenethylamine, amphetamine, and methamphetamine, can also diffuse directly across the cell membrane to varying degrees. Once inside the presynaptic neuron, they may inhibit the reuptake of monoamine neurotransmitters through vesicular monoamine transporter 2 (VMAT2) and release the neurotransmitters stores of synaptic vesicles into the cytoplasm by inducing reverse transport at VMAT2. MRAs can also bind to the intracellular receptor TAAR1 as agonists, which triggers a phosphorylation cascade via protein kinases that results in the phosphorylation of monoamine transporters located at the plasma membrane (i.e., the dopamine transporter, norepinephrine transporter, and serotonin transporter); upon phosphorylation, these transporters transport monoamines in reverse (i.e., they move monoamines from the neuronal cytoplasm into the synaptic cleft).^[1] 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).

Effects

Monoamine releasing agents can have a wide variety of effects depending upon their selectivity for monoamines. Selective serotonin releasing agents such as fenfluramine and related compounds are described as dysphoric and lethargic in lower doses, and in higher doses some hallucinogenic effects have been reported.^[2][3] Less selective serotonergic agents that stimulate an efflux in dopamine, such as MDMA are described as more pleasant, increasing energy, sociability and elevating mood.^[4] Dopamine releasing agents, usually selective for both norepinephrine and dopamine have psychostimulant effect, causing an increase in energy, and elevated mood.^[5] Other variables can significantly affect the subjective effects, such as infusion rate(increasing positive effects of cocaine), and expectancy.^[6] Selectively noradrenergic drugs are minimally psychoactive, but as demonstrated by ephedrine may be distinguished from placebo, and trends towards liking.^[7] They may also be ergogenic,^[8] in contrast to reboxetine which is solely a reuptake inhibitor.^[9][10]

Selectivity

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

As of present, no selective DRAs are known. This is because it has proven extremely difficult to separate DAT affinity from NET affinity and retain releasing efficacy at the same time.^[11] Several selective SDRAs are known however, though these compounds also act as non-selective serotonin receptor agonists.^[12]

Activity profiles

Zdroj:https://en.wikipedia.org?pojem=Monoamine_releasing_agent
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Activity profiles of MRAs (EC₅₀, nM)^[13][14]

Compound	5-HTTooltip Serotonin	NETooltip Norepinephrine	DATooltip Dopamine	Type	Class	Ref
2C-E	>100000	>100000	>100000	IA	Phenethylamine	[15]
2C-I	>100000	>100000	>100000	IA	Phenethylamine	[15]
3-Chloromethcathinone	ND	ND	46.8	ND	Cathinone	[16]
3-Fluoroamphetamine	1937	16.1	24.2	NDRA	Amphetamine	[17]
3-Methylamphetamine	218	18.3	33.3	NDRA	Amphetamine	[17]
4-Fluoroamphetamine	730–939	28.0–37	51.5–200	NDRA	Amphetamine	[17][15]
cis-4-Methylaminorex	53.2	4.8	1.7	NDRA	Aminorex	[18]
4-Methylamphetamine	53.4	22.2	44.1	SNDRA	Amphetamine	[17]
4-Methylphenethylamine	ND	ND	271	ND	Phenethylamine	[16]
4-Methylthiomethamphetamine	21	ND	ND	ND	Amphetamine	[19]
4,4'-Dimethylaminorex	ND	ND	ND	SNDRA	Aminorex	ND
''cis''-4,4'-Dimethylaminorex	17.7–18.5	11.8–26.9	8.6–10.9	SNDRA	Aminorex	[18][20]
''trans''-4,4'-Dimethylaminorex	59.9	31.6	24.4	SNDRA	Aminorex	[20]
5-(2-Aminopropyl)indole	28–104.8	13.3–79	12.9–173	SNDRA	Amphetamine	[12][21]
(''R'')-5-(2-Aminopropyl)indole	177	81	1062	SNRA	Amphetamine	[12]
(''S'')-5-(2-Aminopropyl)indole	ND	ND	ND	SNDRA	Amphetamine	ND
5-Chloro-αMT	16	3434	54	SDRA	Tryptamine	[12]
5-Fluoro-αMT	19	126	32	SNDRA	Tryptamine	[12]
5-MeO-αMT	460	8900	1500	SNDRA	Tryptamine	[15]
5-MeO-DMT	>100000	>100000	>100000	IA	Tryptamine	[15]
6-(2-Aminopropyl)indole	19.9	25.6	164.0	SNDRA	Amphetamine	[21]
Adderall	ND	ND	ND	NDRA	Amphetamine	ND
α-Methyltryptamine	68	79	180	SNDRA	Tryptamine	[15]
Amfepramone (diethylpropion)	>10000	>10000	>10000	PD	Cathinone	[22]
Aminorex	193–414	15.1–26.4	9.1–49.4	SNDRA	Aminorex	[23][18]
Amphetamine	ND	ND	ND	NDRA	Amphetamine	ND
D-Amphetamine	698–1765	6.6–7.2	5.8–24.8	NDRA	Amphetamine	[23][24]
L-Amphetamine	ND	ND	ND	NRA	Amphetamine	ND
β-Ketophenethylamine	ND	ND	208	ND	Phenethylamine	[16]
BDB	180	540	2,300	NDRA	Amphetamine	[15]
Benzylpiperazine	≥6050	62–68	175–600	NDRA	Arylpiperazine	[15][25][14]
Butylamphetamine	ND	ND	IA	ND	Amphetamine	[16]
Cathinone	ND	ND	ND	NDRA	Cathinone	ND
D-Cathinone	ND	ND	ND	NRA	Cathinone	ND
L-Cathinone	2366	12.4	18.5	NDRA	Cathinone	[26]
Chlorphentermine	30.9	>10000	2650	SRA	Amphetamine	[23]
DMPP	26	56	1207	SNRA	Arylpiperazine	[19]
Dopamine	>10000	66.2	86.9	NDRA	Phenethylamine	[23]
DPT	>100000	>100000	>100000	IA	Tryptamine	[15]
Ephedrine	ND	ND	ND	NDRA	Cathinol	ND
D-Ephedrine	>10000	43.1–72.4	236–1350	NDRA	Cathinol	[23]
L-Ephedrine	>10000	218	2104	NRA	Cathinol	[23][26]
Epinephrine	ND	ND	ND	NDRA	Phenethylamine	ND
Ethcathinone	2118	99.3	>1000	NRA	Cathinone	[22]
Ethylamphetamine	ND	ND	296	ND	Amphetamine	[16]
Fenfluramine	79.3–108	739	>10000	SRA	Amphetamine	[23][27][28]
D-Fenfluramine	51.7	302	>10000	SNRA	Amphetamine	[23][27]
L-Fenfluramine	147	>10000	>10000	SRA	Amphetamine	[27][29]
MBDB	540	3300	>100,000	SNRA	Amphetamine	[15]
mCPP	28–38.1	≥1400	63000	SRA	Arylpiperazine	[15][29][30]
MDA	160	108	190	SNDRA	Amphetamine	[28]
(''R'')-MDA	310	290	900	SNDRA	Amphetamine	[28]
(''S'')-MDA	100	50	98	SNDRA	Amphetamine	[28]
MDEA	47	2608	622	SNDRA	Amphetamine	[19]
(''R'')-MDEA	52	651	507	SNDRA	Amphetamine	[19]
(''S'')-MDEA	465	RI	RI	SRA	Amphetamine	[19]
MDMA	49.6–72	54.1–110	51.2–278	SNDRA	Amphetamine	[23][31][21][28]
(''R'')-MDMA	340	560	3700	SNDRA	Amphetamine	[28]
(''S'')-MDMA	74	136	142	SNDRA	Amphetamine	[28]
MDMAR	ND	ND	ND	SNDRA	Aminorex	ND
''cis''-MDMAR	43.9	14.8	10.2	SNDRA	Aminorex	[20]
''trans''-MDMAR	73.4	38.9	36.2	SNDRA	Aminorex	[20]
Mephedrone	118.3–122	58–62.7	49.1–51	SNDRA	Cathinone	[31][24]
Methamnetamine	13	34	10	SNDRA	Amphetamine	[19]
Methamphetamine	ND	ND	ND	NDRA	Amphetamine	ND
D-Methamphetamine	736–1291.7	12.3–13.8	8.5–24.5	NDRA	Amphetamine	[23][31]
L-Methamphetamine	4640	28.5	416	NRA	Amphetamine	[23]
Methcathinone	ND	ND	ND	NDRA	Cathinone	ND
D-Methcathinone	ND	ND	ND	NRA	Cathinone	ND
L-Methcathinone	1772	13.1	14.8	NDRA	Cathinone	[26]
Methylone	234–242.1	140–152.3	117–133.0	SNDRA	Cathinone	[31][24]
Naphthylisopropylamine	3.4	11.1	12.6	SNDRA	Amphetamine	[32]
Norephedrine	ND	ND	ND	NDRA	Cathinol	ND
D-Norephedrine	>10000	42.1	302	NDRA	Cathinol	[26]
L-Norephedrine (phenylpropanolamine)	>10000	137	1371	NRA	Cathinol	[26]
Norepinephrine	>10000	164	869	NDRA	Phenethylamine	[23]
Norfenfluramine	104	168–170	1900–1925	SNRA	Amphetamine	[27][28]
Norpropylhexedrine	ND	ND	ND	NDRA	Cyclohexethylamine	ND
D-Norpropylhexedrine	ND	ND	ND	NRA	Cyclohexethylamine	ND
L-Norpropylhexedrine	ND	ND	ND	NDRA	Cyclohexethylamine	ND
Norpseudoephedrine	ND	ND	ND	NDRA	Cathinol	ND
D-Norpseudoephedrine (cathine)	>10000	15.0	68.3	NDRA	Cathinol	[26]
L-Norpseudoephedrine	>10000	30.1	294	NDRA	Cathinol	[26]
oMPP	175	39.1	296–542	SNDRA	Arylpiperazine	[33][16]
PAL-738	23	65	58