Monoamine releasing agent

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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, namely the amphetamines and related compounds.

Types of MRAs[edit]

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

Mechanism of action[edit]

MRAs cause the release of monoamine neurotransmitters by a complex mechanism of action. First, they enter the presynaptic neuron primarily via membrane transporters, including the dopamine transporter (DAT), norepinephrine transporter (NET), and/or serotonin transporter (SERT). Some, such as amphetamine and methamphetamine, can also diffuse directly across the cell membrane to varying degrees. Next, they inhibit vesicular reuptake of monoamine neurotransmitters by interfering with the vesicular monoamine transporter 2 (VMAT2), as well as cause the VMAT2 to dump vesicular monoamine neurotransmitter stores, and thus produce an accumulation of monoamine neurotransmitters in the cell cytoplasm. Finally, MRAs induce the release of monoamine neurotransmitters by acting as agonists of the TAAR1, which causes the monoamine transporters to reverses their direction of transport. This results in an elevation in levels of monoamine neurotransmitters in the synapse, which then bind to postsynaptic monoamine receptors, resulting in increased monoaminergic neurotransmission.

MRAs also block monoamine transporters both directly, and indirectly as a consequence of TAAR1 activation, and thus behave simultaneously as plasmalemmal reuptake inhibitors of monoamine neurotransmitters.


Selecitivities of MRAs (Ki (nM)):[1][2][3][4][5][6]
Compound NE DA 5-HT
4-Fluoroamphetamine 28 51.5 939
4-Methylamphetamine 22.2 44.1 53.4
Aminorex 54.5 216 1244
D-Amphetamine 7.1 110.3 1,765
Benzylpiperazine 62 175 6,050
Cathine 15.0 68.3 -
L-Cathinone 12.4 18.5 2,366
Chlorphentermine 451 3940 338
L-Ephedrine 43.1 236 >10000
D-Ephedrine 218 2104 >10000
Fenfluramine >10000 >10000 667
Dexfenfluramine >10000 >10000 667
Levfenfluramine >10000 >10000 667
D-Methamphetamine 489 24.5 736
L-Methamphetamine 234 4840 >10000
L-Methcathinone 707 14.8 1772
MDA 108 190 160
MDMA 110 278 72
Naphthylisopropylamine 11.1 12.6 3.4
Norfenfluramine 170 1900 104
Phenmetrazine 50.4 131 7,765
Phentermine 244 1580 >10000
Phenylpropanolamine 89.5 836.6 -
Pseudoephedrine 3112 1988 >10000
Tyramine 72.5 106 1556

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 a 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 and ephedrine, which are selective SRAs and NRAs, respectively. 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.[8]

See also[edit]


  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 2751297. 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. PMID 24796848.