- 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. 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) (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.
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.
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 GABAA and GABAB 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
- 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))
- 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)
- 4-Fluoroamphetamine (4-FA)
- 4-Fluoromethcathinone (4-FMC; Flephedrone)
- 4-Methoxyphenylpiperazine (MeOPP; Paraperazine)
- 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)
- β-Keto-Methylbenzodioxolbutanamine (bk-MBDB; Butylone)
- Benzodioxylbutanamine (BDB)
- Benzylpiperazine (BZP)
- meta-Chlorophenylpiperazine (mCPP)
- Methylbenzodioxolbutanamine (MBDB)
- Methylbenzylpiperazine (MBZP)
- Methylenedioxyamphetamine (MDA)
- Methylenedioxybenzylpiperazine (MDBZP)
- Methylenedioxyethylamphetamine (MDEA)
- Methylenedioxyethylcathinone (MDEC, bk-MDEA; Ethylone)
- Methylenedioxymethamphetamine (MDMA; "Ecstasy", "Adam")
- Methylenedioxymethcathinone (MDMC, bk-MDMA; Methylone)
- Methylenedioxymethoxyamphetamine (MMDA)
- para-Fluorophenylpiperazine (pFPP; Fluoperazine)
- para-Methoxyamphetamine (PMA)
- para-Methoxyethylamphetamine (PMEA)
- para-Methoxymethamphetamine (PMMA)
- para-Methoxymethcathinone (bk-PMMA; Methedrone)
- Trifluoromethylphenylpiperazine (TFMPP)
- 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)
- 5-Methoxytryptamine (5-MT)
- 8-Hydroxydipropylaminotetralin (8-OH-DPAT)
- Ethyltrifluoromethylaminoindane (ETAI)
- Indanylaminopropane (IAP)
- Methoxymethamphetamine (MMA)
- Methoxymethylaminoindane (MMAI)
- Methylenedioxyaminoindane (MDAI)
- Methylenedioxymethylaminoindane (MDMAI)
- Naphthylaminopropane (NAP; PAL-287)
- para-Bromoamphetamine (PBA)
- para-Chloroamphetamine (PCA)
- para-Iodoamphetamine (PIA)
- Trifluoromethylaminoindane (TAI)
Comparison of binding profiles
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.
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Monoamine releasing agents Substituted aminesIndanylaminesIndolylaminesPhenylalkylamines2-Fluoroamphetamine (2-FA) • 2-Hydroxyphenethylamine (2-HO-PEA) • 3-Fluoroamphetamine (3-FA) • 3-Methoxy-4-methylamphetamine (MMA) • 3-Methoxyamphetamine • 3-Methoxymethamphetamine (MMMA) • 3-Methylamphetamine (3-MA) • 4-Bromoamphetamine (PBA) • 4-Chloroamphetamine (PCA) • 4-Ethoxyamphetamine • 4-Ethylamphetamine (4-EA) • 4-Fluoroamphetamine (4-FA) • 4-Fluoromethamphetamine (4-FMA) • 4-Hydroxyamphetamine (4-HA) • 4-Iodoamphetamine (PIA) • para-Methoxyamphetamine (PMA) • para-Methoxyethylamphetamine (PMEA) • 4-Methoxymethamphetamine (PMMA) • 4-Methylamphetamine (4-MA) • 4-Methylmethamphetamine (4-MMA) • 4-Methylthioamphetamine (4-MTA) • 5-APDB • α-Ethylphenethylamine (α-Et-PEA) • Alfetamine • Amfecloral • Amfepentorex • Amphetamine • β-Methylphenethylamine (β-Me-PEA) • Amphetaminil • BDB • Benfluorex • Benzphetamine • BOH • Brephedrone • Buphedrone • Butylone • Cathine • Cathinone • Chlorphentermine • Clofenciclan • Cloforex • Clortermine • Clobenzorex • Cypenamine • Diethylcathinone (DEC) • Dimethoxyamphetamine (DMA) • Dimethoxymethamphetamine (DMMA) • Dimethylamphetamine (DMeA) • Dimethylcathinone (DMC) • Dopamine • EBDB • Ephedrine (EPH) • Epinephrine (Adrenaline) • Epinine • Ethcathinone • Ethylamphetamine • Ethylone • Famprofazone • Fencamfamine • Fencamine • Fenethylline • Fenfluramine • Fenproporex • Feprosidnine • Flephedrone • Fludorex • Furfenorex • Gilutensin • Hordenine • Indanorex • Lefetamine • Lisdexamfetamine • Lophophine • MBDB • MDA • MDEA • MDMA • MDMPEA • MDOH • MDPEA • Mefenorex • Mephedrone • Mephentermine • Methamphetamine • Methcathinone • Methedrone • Methoxyphenamine • Methylone • MMDA • MMDMA • Norepinephrine (Noradrenaline) • Norfenfluramine • Octopamine • Ortetamine • Oxilofrine • Paredrine • Phenethylamine (PEA) • Phenpentermine • Phenpromethamine • Phentermine • Phenylpropanolamine (PPA) • Pholedrine • Phthalimidopropiophenone • Propylamphetamine • Pseudoephedrine (PSE) • Selegiline • Tiflorex • Tranylcypromine • Tyramine • Xylopropamine • Zylofuramine Amine containing2-Benzylpiperidine (2-BP) • 4-Benzylpiperidine (4-BP) Unclassified/unsortedIndeloxazine • Tramadol • Viqualine Neuromodulation Types Classessee Enzyme inhibitionCannabinoid receptor agonist • Cannabinoid receptor antagonistOtherMiscellaneous
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