α-Methyldopamine (α-Me-DA), also known as 3,4-dihydroxyamphetamine (3,4-DHA or HHA) or as catecholamphetamine, is a

research chemical Research chemicals are chemical substances which scientists use for medical and scientific research purposes. One characteristic of a research chemical is that it is for laboratory research use only; a research chemical is not intended for human ...

of the

catecholamine A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Cate ...

and

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 ...

families. It is a

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 ...

and a

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

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 MDA. The ''bis''- glutathionyl

of α-methyldopamine is slightly

neurotoxic Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...

when directly injected into the brain's ventricles.

Role in MDMA-induced serotonergic neurotoxicity

Interest in α-methyldopamine lies in the fact that 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxy-''N''-methylamphetamine (MDMA) may not themselves be responsible for their serotonergic

neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...

, as an

intracerebroventricular injection Intracerebroventricular injection (often abbreviated as ICV injection) is a route of administration for drugs via injection into the cerebral ventricles so that it reaches the cerebrospinal fluid (CSF). This route of administration is often used ...

does not appear to cause neurotoxicity. While many studies suggest

excitotoxicity In excitotoxicity, neuron, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamic acid, glutamate become pathologically high, resulting in excessive stimulation of cell surface recept ...

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

as likely mechanisms, which may be an effect of MDMA itself, this has led to the search for other mechanisms for the observed toxicity 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, ...

axons and subsequent reduction in

(5-HT) and 5-HIAA (its major metabolite in the body) ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' following administration. A common theory follows that a

of MDA and MDMA in the periphery must be responsible, and several have been cited as responsible. Although α-methyldopamine is widely cited as the source of this neurotoxicity in a number of lay sources, McCann, ''et al.'' (1991), demonstrated that the major metabolites α-methyldopamine and 3-''O''-methyl-α-methyldopamine (3-O-Me-α-MeDA or HMA) did not produce neurotoxicity. It was first demonstrated, in 1978, by Conway ''et al.'' and possibly others that, while α-methyldopamine caused acute decreases in the levels of

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

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 some areas of the brain in excess of 75%, levels returned to baseline within 12hours, indicating that α-methyldopamine could not be responsible for the toxic effects observed. However, the story complicates as α-methyldopamine readily oxidizes to the ''o''-

quinone The quinones are a class of organic compounds that are formally "derived from aromatic compounds benzene.html" ;"title="uch as benzene">uch as benzene or naphthalene] by conversion of an even number of –CH= groups into –C(=O)– groups with ...

and reacts with

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

antioxidant Antioxidants are Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...

s in the body, such as

glutathione Glutathione (GSH, ) is an organic compound with the chemical formula . It is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources ...

(GSH). It was demonstrated by Miller ''et al.'' (1997), that 5-(glutathion-''S''-yl)-α-methyldopamine and 5-(''N''-acetylcystein-''S''-yl)-α-methyldopamine produced similar effects to the parent compound, but did not induce neurotoxicity when injected intracerebroventricularly. However, the derivative metabolite 2,5-''bis''-(glutathion-''S''-yl)-α-methyldopamine (injected at ~1.5times the usual per-kg MDMA dose) did in fact induce neurotoxicity, providing initial evidence that this metabolite may be the source of neuronal toxicity following the administration of MDA and MDMA, and the subsequent reduction in serotonergic

axon An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...

s. In spite of the above, there is also evidence that metabolites may not be involved in the neurotoxicity of MDMA or related drugs and that the neurotoxicity is intrinsic to their

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

, specifically simultaneous induction of serotonin and dopamine release. Accordingly, while single injections of MDMA directly into the brain have not been found to produce neurotoxicity, slow infusions of MDMA into the brain over 1hour do result in signs of neurotoxicity.

Chemistry

α-Methyldopamine, also known as 3,4-dihydroxy-α-methylphenethylamine or as 3,4-dihydroxyamphetamine, is a

substituted phenethylamine Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative (chemistry), derivative compounds of phenethylamine ...

, and

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

. It is the α-

methylated Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These term ...

or amphetamine analogue of

(3,4-dihydroxyphenethylamine). Analogues of α-methyldopamine include corbadrine (levonordefrin; α-methylnorepinephrine; 3,4,β-trihydroxyamphetamine), dioxifedrine (α-methylepinephrine; 3,4,β-trihydroxy-''N''-methylamphetamine), and

hydroxyamphetamine Hydroxyamphetamine may refer to: * β-Hydroxyamphetamine (phenylisopropanolamine; two chiral centers and four possible stereoisomers) ** Phenylpropanolamine (racemic phenylpropanolamine; norephedrine; (1''R'',2''S''/1''S'',2''R'')-β-hydroxyampheta ...

(norpholedrine; α-methyltyramine; 4-hydroxyamphetamine)

References

{{DEFAULTSORT:Methyldopamine, alpha- Adrenergic receptor agonists Catecholamines Dopamine agonists Human drug metabolites Human pathological metabolites Monoaminergic neurotoxins Norepinephrine-dopamine releasing agents Peripherally selective drugs Substituted amphetamines Sympathomimetics

Role in MDMA-induced serotonergic neurotoxicity

Chemistry

See also

References