A dopamine releasing agent (DRA) is a type of

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

which induces the

release Release may refer to: * Art release, the public distribution of an artistic production, such as a film, album, or song * Legal release, a legal instrument * News release, a communication directed at the news media * Release (ISUP), a code to i ...

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

in the

body Body may refer to: In science * Physical body, an object in physics that represents a large amount, has mass or takes up space * Body (biology), the physical material of an organism * Body plan, the physical features shared by a group of anim ...

and/or

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

. No selective DRAs are currently known. However, non-selective DRAs, including

norepinephrine–dopamine releasing agent A norepinephrine–dopamine releasing agent (NDRA) is a type of drug which induces the synapse, release of norepinephrine (and epinephrine) and dopamine in the body and/or brain. Many of these are amphetamine type stimulants. Examples Examples ...

s (NDRAs) like

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

and

methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

serotonin–norepinephrine–dopamine releasing agent A serotonin–norepinephrine–dopamine releasing agent (SNDRA), also known as a triple releasing agent (TRA), is a type of drug which induces the release of serotonin, norepinephrine/epinephrine, and dopamine in the brain and body. SNDRAs produc ...

s (SNDRAs) like

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor Psychedelic drug, psychedelic properties. In studies, it has been used ...

and

mephedrone Mephedrone, also known as , , and , is a synthetic stimulant drug belonging to the amphetamine and cathinone classes. It is commonly referred to by slang names such as drone, , white magic, meow meow, and bubble. Chemically, it is similar to ...

, and

serotonin–dopamine releasing agent A serotonin–dopamine releasing agent (SDRA) is a type of drug which induces the synapse, release of serotonin and dopamine in the body and/or brain. SDRAs are rare, as it has proven extremely difficult to dissociate dopamine and norepinephri ...

s (SDRAs) like 5-chloro-αMT and

BK-NM-AMT BK-NM-AMT, or βk-NM-αMT, also known as β-keto-''N''-methyl-αMT or α,''N''-dimethyl-β-ketotryptamine, as well as 3-indoylmethcathinone, is a serotonin–dopamine releasing agent (SDRA) and putative entactogen of the tryptamine, α-alkyltryp ...

, are known. A closely related type of drug is a

dopamine reuptake inhibitor A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dop ...

(DRI). In contrast to the case of DRAs, many selective DRIs are known. Examples of selective DRIs include

amineptine Amineptine, formerly sold under the brand name Survector among others, is an atypical antidepressant of the tricyclic antidepressant (TCA) family. It acts as a selective and mixed dopamine reuptake inhibitor and releasing agent, and to a le ...

modafinil Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant and wakefulness-promoting agent, eugeroic (wakefulness promoter) medication used primarily to treat narcolepsy, a sleep disorder characteri ...

, and

vanoxerine Vanoxerine is an investigational drug which is being evaluated for the treatment of heart arrhythmias and cocaine dependence. Vanoxerine is a piperazine derivative which has multiple pharmacological activities including acting as an dopamine re ...

Selectivity

No selective and robust DRAs are currently known. The lack of known selective DRAs is related to the fact that it has proven extremely difficult to separate

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

(DAT)

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

from

norepinephrine transporter The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene. NET is a monoamine transporter and is responsible for the sodium ...

(NET) affinity and retain releasing capability at the same time. Despite evaluation of over 350compounds, it was reported in 2007 that it had been virtually impossible to dissociate norepinephrine and dopamine release. By 2014, still no selective DRAs had been identified, despite approximately 1,400compounds having been screened. Similarly, while moderately selective

norepinephrine releasing agent A norepinephrine releasing agent (NRA), also known as an adrenergic releasing agent, is a catecholaminergic type of drug that induces the release of norepinephrine (noradrenaline) and epinephrine (adrenaline) from the pre-synaptic neuron into ...

s (NRAs) are known (e.g., ~10- to 20-fold preference or norepinephrine over dopamine release), no highly selective NRAs had been identified. The inability to identify selective DRAs has been attributed to the strong

phylogenetic In biology, phylogenetics () is the study of the evolutionary history of life using observable characteristics of organisms (or genes), which is known as phylogenetic inference. It infers the relationship among organisms based on empirical dat ...

similarities between the DAT and NET. Although no selective DRAs have been identified, selective SDRAs, albeit with concomitant

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...

agonism Agonism (from Greek 'struggle') is a political and social theory that emphasizes the potentially positive aspects of certain forms of conflict. It accepts a permanent place for such conflict in the political sphere, but seeks to show how indivi ...

, were described in 2014. SDRAs without known serotonin receptor agonism, such as

, were described by 2019. Although no selective DRAs are currently known, many non-selective

releasing agent A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrati ...

s of both

and

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

(

s or NDRAs) and of

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

, norepinephrine, and dopamine (

s or SNDRAs) are known. Examples of major NDRAs include the

psychostimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition ...

and

, while an example of an SNDRA is the

entactogen Entactogens, also known as empathogens or connectogens, are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, connectedness, emotional openness—that is, empathy—as particularly observe ...

methylenedioxymethamphetamine 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor psychedelic properties. In studies, it has been used alongside psych ...

(MDMA). These drugs are frequently used for recreational purposes and encountered as

drugs of abuse Substance misuse, also known as drug misuse or, in older vernacular, substance abuse, is the use of a drug in amounts or by methods that are harmful to the individual or others. It is a form of substance-related disorder, differing definitions ...

. DRAs, including NDRAs and theoretically also selective DRAs, have medical utility in the treatment of

attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

(ADHD). SDRAs, for instance 5-chloro-αMT, are less common and are not selective for dopamine release, but have also been developed.

Tryptamine Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the firs ...

s like 5-chloro-αMT are the only known releaser scaffold that consistently release dopamine more potently than norepinephrine.

Therapeutic applications

Selective DRAs might have different clinical effects in the treatment of

(ADHD) than the NDRAs like

s and

norepinephrine–dopamine reuptake inhibitor A norepinephrine–dopamine reuptake inhibitor (NDRI) is a type of drug that inhibits the reuptake of the monoamine neurotransmitters norepinephrine and dopamine and thereby increases extracellular levels of these neurotransmitters and nor ...

s (NDRIs) like

methylphenidate Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...

that are currently used. For example, they might have improved therapeutic selectivity by reducing or eliminating the

cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...

and sympathomimetic

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of NDRAs.

Examples of DRAs

Amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

s like

dextroamphetamine Dextroamphetamine (international nonproprietary name, INN: dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narc ...

and

dextromethamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational or performance-enhancing drug and less commonly as a second-line treatment for attention deficit hyperactivity di ...

are fairly balanced NDRAs but release norepinephrine about 2- to 3-fold more potently than dopamine. However, other studies found that dextroamphetamine and dextromethamphetamine were roughly equipotent or slightly favored dopamine in terms of norepinephrine versus dopamine release. A number of potentially more well-balanced NDRAs, including

levomethcathinone Methcathinone (α-methylamino-propiophenone or ephedrone) (sometimes called "cat" or "jeff" or "catnip" or "M-Kat" or "kat" or "intash") is a monoamine alkaloid and psychoactive stimulant, a substituted cathinone. It is used as a recreational d ...

(''l''-MC),

3-chloroamphetamine 3-Chloroamphetamine (3-CA; code name PAL-304), also known as ''meta''-chloroamphetamine (MCA), is a psychostimulant of the amphetamine family and a serotonergic neurotoxin related to ''para''-chloroamphetamine (PCA; 4-chloroamphetamine). The d ...

(3-CA; PAL-304),

3-chloromethcathinone 3-Chloromethcathinone (3-CMC), also known as clophedrone, is a synthetic substance belonging to the Substituted cathinone, cathinone class of Psychoactive drug, psychoactive compounds. It is very similar in structure to other methcathinone deri ...

(3-CMC; clophedrone; PAL-434), and 2-phenylmorpholine (2-PM; PAL-632), are known, and all appear to be roughly equipotent in inducing dopamine versus norepinephrine release. A few NDRAs, including ''cis''-4-methylaminorex (''cis''-4-MAR),

3-chlorophenmetrazine 3-Chlorophenmetrazine (3-CPM; code name PAL-594) is a recreational designer drug with stimulant effects. It is a substituted phenylmorpholine derivative, closely related to better known drugs such as phenmetrazine and 3-fluorophenmetrazine (3-FP ...

(3-CPM; PAL-594), and

naphthylmetrazine Naphthylmetrazine (code name PAL-704), also known as 3-methyl-2-(2′-naphthyl)morpholine, is a monoamine releasing agent (MRA) and monoamine reuptake inhibitor (MRI) of the phenylmorpholine and naphthylaminopropane families related to phenmetr ...

(PAL-704), appear to release dopamine about 2- to 3-fold more potently than norepinephrine, and hence may be among the most dopamine-selective NDRAs known.

Pemoline Pemoline, formerly sold under the brand name Cylert among others, is a stimulant medication which was used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy,- it has since been discontinued in most countries due ...

, which is structurally related to the

aminorex Aminorex, sold under the brand names Menocil and Apiquel among others, is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension (PPH). In the United States, aminorex is a ...

drugs, is a stimulant used to treat ADHD which is said to act as a selective DRI and DRA, but it is said to only weakly stimulate dopamine release. There is reportedly some, albeit mixed, ''

in-vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') studies are performed with cells or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology and its subdis ...

'' evidence that the

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

and modestly selective DRI

may, in addition to inhibiting the reuptake of dopamine, selectively induce the presynaptic release of dopamine without affecting release of norepinephrine or serotonin. However, amineptine is larger than the known small structural size limit of

monoamine releasing agent A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrati ...

s, suggesting that it may not in fact be a DRA. Although no definite selective DRAs have been described, one possible exception is

2-fluoromethcathinone 2-Fluoromethcathinone (2-FMC), also known as 2-flephedrone, is a psychostimulant and designer drug of the cathinone family. It acts as a dopamine and norepinephrine releasing agent (NDRA). Pharmacology The drug has an for dopamine release of ...

(2-FMC). It has an for dopamine release of 48.7nM but induces only 85% release of

at a concentration of 10μM. For comparison, the values of the NDRA

methcathinone Methcathinone (α-methylamino-propiophenone or ephedrone) (sometimes called "cat" or "jeff" or "catnip" or "M-Kat" or "kat" or "intash") is a monoamine alkaloid and psychoactive stimulant, a substituted cathinone. It is used as a recreational d ...

are 49.9nM for dopamine release and 22.4nM for norepinephrine release and it induces 100% release of norepinephrine at a concentration of 10μM. Hence, compared to methcathinone, 2-FMC appears to be relatively more selective or

efficacious Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made between ...

for induction of dopamine release over norepinephrine release. In any case, the of 2-FMC for induction of norepinephrine release does not seem to be available. Moreover, in another instance, the related drug

3-methoxymethcathinone 3-Methoxymethcathinone (3-MeOMC), also known as ''meta''-methoxymethcathinone (''m''-MeOMC), is a designer drug of the substituted cathinone family described as a stimulant. Similarly to other cathinones, it acts as a monoamine releasing agent, ...

(3-MeOMC) released only 68% norepinephrine at 10μM, yet an value of the drug of 111nM for induction of norepinephrine release was provided in another publication.

Mechanism of action

References

External links