Monoamine releasing agent

Amphetamine, the prototypical monoamine releasing agent, which acts on norepinephrine and dopamine.

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

There are a variety of different types of MRAs, including:

Mechanism of action

MRAs cause the release of monoamine neurotransmitters by a complex mechanism of action. First, they 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 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 also bind to the intracellular receptor TAAR1 as agonists, which produces reuptake inhibition and reverse transport at the plasma membrane transporters (DAT, NET, and SERT) as a result. 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).


Selecitivities of MRAs (Ki (nM)):[1][2][3][4][5][6]
Compound NE DA 5-HT
4-Fluoroamphetamine 28.0 51.5 939
4-Methylamphetamine 22.2 44.1 53.4
4-Methylmethcathinone 62.7 49.1 118.3
Aminorex 26.4 49.4 193
D-Amphetamine 7.07 24.8 1765
Benzylpiperazine 62 175 6050
Cathine 15.0 68.3 >10000
L-Cathinone 12.4 18.5 2366
Chlorphentermine >10000 2650 30.9
L-Ephedrine 43.1 236 >10000
D-Ephedrine 218 2104 >10000
Fenfluramine 739 >10000 79.3
Dexfenfluramine 302 >10000 51.7
Levfenfluramine >10000 >10000 147
D-Methamphetamine 12.3 24.5 736
L-Methamphetamine 28.5 416 4640
L-Methcathinone 13.1 14.8 1772
MDA 108 190 160
MDMA 110 278 72
Methylone 152.3 133 242.1
Naphthylisopropylamine 11.1 12.6 3.4
Norfenfluramine 168 1925 104
Phenmetrazine 50.4 131 7765
Phentermine 39.4 262 3511
Phenylpropanolamine 89.5 836.6 >10000
L-Pseudoephedrine 224 1988 >10000
Tyramine 40.6 119 2775

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.[7] Several selective SDRAs are known however, though these compounds also act as non-selective serotonin receptor agonists.[8]

See also


  1. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin.". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707.
  2. Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates.". Curr Top Med Chem. 6 (17): 1845–59. doi:10.2174/156802606778249766. PMID 17017961.
  3. Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, et al. (2003). "In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates.". J Pharmacol Exp Ther. 307 (1): 138–45. doi:10.1124/jpet.103.053975. PMID 12954796.
  4. Rothman RB, Blough BE, Woolverton WL, Anderson KG, Negus SS, Mello NK, et al. (2005). "Development of a rationally designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration.". J Pharmacol Exp Ther. 313 (3): 1361–9. doi:10.1124/jpet.104.082503. PMID 15761112.
  5. Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (2005). "Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs.". J Pharmacol Exp Ther. 313 (2): 848–54. doi:10.1124/jpet.104.080101. PMID 15677348.
  6. Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 8 November 2013.
  7. Rothman RB, Blough BE, Baumann MH (2007). "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". The AAPS Journal. 9 (1): E1–10. doi:10.1208/aapsj0901001. PMC 2751297Freely accessible. PMID 17408232.
  8. Banks ML, Bauer CT, Blough BE, et al. (June 2014). "Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys". Experimental and Clinical Psychopharmacology. 22 (3): 274–84. doi:10.1037/a0036595. PMC 4067459Freely accessible. PMID 24796848.
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