Releasing agent

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

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. The vast majority of currently known releasing agents work on the monoamine neurotransmitters serotonin, norepinephrine, and dopamine.

Mechanism of action

Releasing agents cause the release of monoamine neurotransmitters by a complex mechanism of action. First, they penetrate the presynaptic cell primarily by being taken up as a substrate by binding to the plasmalemmal transporter(s), 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 the 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 the plasmalemmal transporter(s) via a process known as phosphorylation, allowing the neurotransmitter(s) to flow out from the cytoplasm into the nerve terminal or synapse. This leads to an increase in the extracellular concentrations of dopamine, norepinephrine, and/or serotonin, and therefore an increase in overall monoaminergic neurotransmission.

Releasing agents also function as reuptake inhibitors to varying extents due to their competitive plasmalemmal transporter affinity and binding, and this property plays a role in their overall effects.

Neurotoxicity

A number of releasing agents, notably many of those derived from amphetamine, have been found to be neurotoxic to serotonin and/or dopamine neurons via damage to axons and dendrites, enzymes, mitochondria, DNA, plasmalemmal and vesicular transporters, and the cell membrane, ultimately causing cell death or apoptosis as a result. Examples include amphetamine, methamphetamine, MDMA, fenfluramine, and PCA, among others. In contrast, piperazine, aminoindane, aminotetralin, and oxazoline releasing agents, as well as those from various other chemical families, are considered to be either significantly less toxic, or fully non-toxic in comparison, depending varyingly on the compound in question.^{[citation needed]}

The neurotoxicity of some of these drugs is believed to be caused by oxidative stress induced by the generation of reactive oxygen species or free radicals, highly reactive particles that rip apart proteins and induce chain reactions of destruction. The free radicals are thought to be generated as byproducts when either the base compound or one or more of its metabolites are broken down by the enzymes monoamine oxidase (MAO-B) and/or cyclooxygenase (COX), among others, from within the presynaptic cell. Hyperthermia and simultaneous serotonin and dopamine release may play a major role in augmenting the damage as well.

These observations are supported by the facts that antioxidants such as ascorbic acid, MAO-B inhibitors like selegiline, drugs that induce hypothermia such as 5-HT₂, D₂, β-adrenergic, and NMDA receptor antagonists, as well as GABA_A and GABA_B receptor agonists, and serotonin reuptake inhibitors and dopamine reuptake inhibitors, respectively, are neuroprotective, and can help reduce damage caused by neurotoxic releasing agents.

List of releasing agents

Natural compounds

• Cathine (found in Catha edulis (Khat))
• Cathinone (found in Catha edulis (Khat))
• Ephedrine (found in Ephedra sinica (Ephedra))
• Pseudoephedrine (Sudafed) (found in Ephedra sinica (Ephedra))

Pharmaceutical drugs

• Amphetamines
  • Amphetamine (Adderall, Dexedrine; "Speed")
  • Benzphetamine (Didrex)
  • Chlorphentermine (Apsedon, Desopimon, Lucofen)
  • Diethylcathinone (Tenuate)
  • Ethylamphetamine (Apetinil)
  • Fenfluramine (Pondimin, Fen-Phen, Redux)
  • Levomethamphetamine (Vicks Vapor Inhaler)
  • Lisdexamphetamine (Vyvanse)
  • Methamphetamine (Desoxyn; "Meth", "Crank", "Crystal")
  • Methylphenidate (Ritalin, Concerta, Focalin)
  • Norfenfluramine (metabolite of fenfluramine)
  • Phentermine (Fastin, Fen-Phen)
  • Phenylpropanolamine (PPA; Acutrim, Dexatrim)
  • Selegiline (L-Deprenyl; Eldepryl, Zelapar, Emsam)
• Cycloalkylamines
  • Cyclopentamine (Cyclosal, Nazett, Sinos)
  • Propylhexedrine (Benzedrex)
  • Tranylcypromine (Parnate, Jatrosom)
• Morpholines
  • Phendimetrazine (Bontril)
  • Phenmetrazine (Preludin)
• Oxazolines
  • Aminorex (Menocil)
  • Fenozolone (Ordinator)
  • Pemoline (Cylert)
• Piperazines
  • Befuraline (DIV-154)
  • Fipexide (Attentil, Vigilor)
  • Piberaline (Trelibet)
• Tryptamines
  • α-Ethyltryptamine (AET; Monase)^[2]
  • α-Methyltryptamine (AMT; Indopan)^[3][4]
• Others
  • Indeloxazine (Elen, Noin)^[5]
  • Tramadol (Ultram, Tramal)^[6][7][8]

Designer drugs

• 4-Fluoroamphetamine (4-FA)^[3]
• 4-Fluoromethcathinone (4-FMC; Flephedrone)
• 4-Methoxyphenylpiperazine (MeOPP; Paraperazine)^[3]
• 4-Methylaminorex (4-MAR; "Ice", "EU4EUH")
• 4-Methylmethcathinone (4-MMC; Mephedrone)
• 4-Methylthioamphetamine (4-MTA)
• 5-Methoxyalphaethyltryptamine (5-MeO-AET)
• 5-Methoxyalphamethyltryptamine (5-MeO-AMT)^[3]
• β-Keto-Methylbenzodioxolbutanamine (bk-MBDB; Butylone)
• Benzodioxylbutanamine (BDB)^[3]
• Benzylpiperazine (BZP)^[9]
• meta-Chlorophenylpiperazine (mCPP)^[3][10][11]
• Methcathinone
• Methylbenzodioxolbutanamine (MBDB)
• Methylbenzylpiperazine (MBZP)
• Methylenedioxyamphetamine (MDA)
• Methylenedioxybenzylpiperazine (MDBZP)
• Methylenedioxyethylamphetamine (MDEA)
• Methylenedioxyethylcathinone (MDEC, bk-MDEA; Ethylone)
• Methylenedioxymethamphetamine (MDMA; "Ecstasy", "Adam")
• Methylenedioxymethcathinone (MDMC, bk-MDMA; Methylone)^[3]
• Methylenedioxymethoxyamphetamine (MMDA)
• para-Fluorophenylpiperazine (pFPP; Fluoperazine)
• para-Methoxyamphetamine (PMA)
• para-Methoxyethylamphetamine (PMEA)
• para-Methoxymethamphetamine (PMMA)
• para-Methoxymethcathinone (bk-PMMA; Methedrone)
• Trifluoromethylphenylpiperazine (TFMPP)^[9]

Research compounds

• 2-Aminodilin (2-AD)
• 2-Aminoindane (2-AI)
• 2-Aminotetralin (2-AT)
• 4-Benzylpiperidine (4-BP)
• 4-Methylamphetamine (4-MA)
• 4-Methylmethamphetamine (4-MMA)
• 5-Aminopropyldihydrobenzofuran (5-APDB)
• 5-Carboxamidotryptamine (5-CT)^[12]
• 5-Methoxytryptamine (5-MT)^[12]
• 8-Hydroxydipropylaminotetralin (8-OH-DPAT)^[12]
• Clominorex
• Cyclazodone
• Cypenamine
• D-Deprenyl
• Dimethylamphetamine
• Ethyltrifluoromethylaminoindane (ETAI)
• Fluminorex
• Indanylaminopropane (IAP)
• Methoxymethamphetamine (MMA)
• Methoxymethylaminoindane (MMAI)
• Methylenedioxyaminoindane (MDAI)
• Methylenedioxymethylaminoindane (MDMAI)
• Naphthylaminopropane (NAP; PAL-287)
• para-Bromoamphetamine (PBA)
• para-Chloroamphetamine (PCA)
• para-Iodoamphetamine (PIA)
• Propylamphetamine
• Thozalinone
• Trifluoromethylaminoindane (TAI)

Trace amines

• Octopamine^[13]
• Phenethylamine (PEA)
• Tryptamine^[12]
• Tyramine^[13]

Comparison of binding profiles

The selectivities of a number of releasing agents have been compared below:^{[14][15][16][17][18]}

Compound	NA (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
Naphthylaminopropane	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.

See also

• Reuptake inhibitor

References

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