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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, namely the 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 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 uptake of the neurotransmitter by interfering with a vesicular transporter such as vesicular monoamine transporter 2 (VMAT2)[1] (via binding or pH-gradient), and thus inhibit the repackaging of the neurotransmitter(s) from the cytoplasm into vesicles. Finally, MRAs reverse the action of monoamine reuptake transporter(s) via a process known as phosphorylation, allowing the neurotransmitter(s) to flow out from the cytoplasm into the nerve terminal or synapse. The result is increased monoaminergic neurotransmission. The postsynaptic effect is enhanced due to the agents' interaction with reuptake transporters; one method by which the action of monoamines is terminated is via reuptake into the presynaptic neuron, and disruption of this process causes further increases in extracellular monoamine concentration.


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, methamphetamine is a potent MRA of norepinephrine and dopamine but only a very weak releaser of serotonin (~30- and 60-fold less than dopamine and norepinephrine, respectively) and MBDB is a fairly balanced releaser of serotonin and norepinephrine 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 releasing agents of serotonin and norepinephrine, respectively.

As of present, no selective DRAs are known. This is because it has proven virtually impossible to separate DAT affinity from NET affinity and retain releasing efficacy at the same time.[2] Accordingly, no known selective SDRAs are known either; though, UWA-101, a serotonin-dopamine reuptake inhibitor,[3] is an amphetamine derivative as well as analogue of MDMA and could possess some releasing efficacy.

Release affinities of selected compounds

The selectivities of a number of MRAs have been compared below:[4][5][6][7][8][9]

Compound NE (Release) DA (Release) 5-HT (Release)
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

The values above are expressed as equilibrium dissociation constants (Ki(nM)). Lower values correspond to higher binding at the site, or in other words, less is more. NE, DA, and 5-HT correspond to the abilities of the compounds to induce the release of norepinephrine, dopamine, and serotonin, respectively. All compounds listed are racemic unless noted otherwise.

See also


  1. ^ Question: Is release restricted to MAs only?
  2. ^ 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. PMC 2751297. PMID 17408232. doi:10.1208/aapsj0901001. 
  3. ^ Johnston TH, Millar Z, Huot P, et al. (February 2012). "A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances l-DOPA benefit in parkinsonian primates". FASEB J. 26 (5): 2154–63. PMID 22345403. doi:10.1096/fj.11-195016. 
  4. ^ 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. PMID 11071707. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. 
  5. ^ Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates.". Curr Top Med Chem 6 (17): 1845–59. PMID 17017961. doi:10.2174/156802606778249766. 
  6. ^ 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. PMID 12954796. doi:10.1124/jpet.103.053975. 
  7. ^ 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. PMID 15761112. doi:10.1124/jpet.104.082503. 
  8. ^ 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. PMID 15677348. doi:10.1124/jpet.104.080101. 
  9. ^ Roth, BL; Driscol, J (12 January 2011). Database"i"PDSP K. 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. 
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