Releasing agent

Releasing agent


A releasing agent (RA), or simply releaser, is a drug that induces the release of a neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs use neurotransmitter release to exert their psychological and physiological effects, namely the amphetamines and related compounds. Virtually all currently known releasing agents affect the monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE), and/or dopamine (DA), and as such, they are often referred to more specifically as monoamine releasing agents (MRAs).

Mechanism of action

Releasing agents 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, releasing agents 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.

Selectivity

Releasing agents 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 releasing agent 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 dopamine releasing agents 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 serotonin and dopamine releasing agents 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 efficacies of selected compounds

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

Compound NE (Release) DA (Release) 5-HT (Release)
4-Fluoroamphetamine 28 51.5 939
4-Methylamphetamine 22.2 44.1 53.4
Aminorex 26.4 49.4 193
(d)-Amphetamine 7.07 24.8 1,765
Benzylpiperazine 62 175 6,050
Cathine 15.0 68.3 -
(l)-Cathinone 12.4 18.5 2,366
Chlorphentermine - 2,650 30.9
Ephedrine 130.5 1,170 -
Fenfluramine 739 - 79.3
(d)-Methamphetamine 12.3 24.5 736
(l)-Methamphetamine 28.5 416 4,640
(l)-Methcathinone 13.1 14.8 1,772
MDA 108 190 160
MDMA 110 278 72
Naphthylisopropylamine 11.1 12.6 3.4
Norfenfluramine 168 1,925 104
Phenmetrazine 50.4 131 7,765
Phentermine 39.4 262 3,511
Phenylpropanolamine 89.5 836.6 -
Pseudoephedrine 2,158 5,556.6 -
Tyramine 40.6 119 2,775

The values above are expressed as equilibrium dissociation constants (EC50 (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.

List of releasing agents

Natural compounds
Pharmaceutical drugs
Designer drugs
Research compounds
Trace amines

See also

References