Alpha-Methyldopamine
Encyclopedia
α-Methyldopamine also known as 3,4-dihydroxyamphetamine (3,4-DHA), is a neurotoxin
and research chemical of the phenethylamine
and amphetamine
chemical classes. It is a metabolite
of various amphetamine derivatives such as amphetamine
itself, methamphetamine
, and MDMA ("Ecstasy"), MDA
and has been suggested to play significant role in their neurotoxic effects on monoaminergic neuron
s. Further study has suggested that, alpha-methyldopamine itself is not directly responsible for the damaging effects, but a specific reaction between alpha-methyldopamine and one of the bodies endogenous antioxidants -glutathione
, may produce 2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine, which has been demonstrated in laboratory animals to cause the same neurotoxic effects seen by related stimulants and empathogens.
The basis of this idea is in the observation that MDA
and MDMA may not themselves be responsible for their neurotoxicity, as an intracerebroventricular injection (injection directly into the brain itself) does not appear to cause neurotoxicity. While many studies cite excitotoxicity
, or oxidative stress
as likely mechanisms, which may be an effect of the chemical itself, this has led to the search for other mechanisms for the observed toxicity of serotonin
neurons and subsequent reduction in 5-HT (Serotonin) and 5-HIAA (its major metabolite in the body) in vivo following administration. A common theory follows that a metabolite in the periphery must be responsible, and several have been cited as responsible. Although, alpha-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 alpha-methyldopamine (α-MeDA) and 3-O-methyl-α-methyldopamine (3-O-Me-α-MeDA) did not produce neurotoxicity.
It was first demonstrated, in 1978, by Conway, et al. and possibly others that, while alpha-methyldopamine caused acute decreases in the levels of neuronal dopamine, in some areas of the brain in excess of 75%, levels returned to baseline within 12 hours, indicating that alpha-methyldopamine would not be responsible for the toxic effects observed.
However, the story complicates as alpha-methyldopamine readily oxidizes to the o-quinone
and reacts with endogenous antioxidants in the body, such as glutathione
(GSH). The mechanism of action behind amphetamines and their related compounds, causes the normally encapsulated neurotransmitters to be released from their oxidative vesicle within the neuron into the reductive environment of the cell cystol. This sudden release of oxidative molecules into the cell puts it under oxidative stress. As Glutathione is the major endogenous anti-oxidant produced in the body to protect against oxidative stress
and xenobiotics (foreign compounds), it likely plays at least some role in the neutralization of the suddenly released catecholamines (Dopamine and Norepinephrine), and Serotonin, as well as the breakdown of amphetamine
, methamphetamine
, MDA
, MDMA, and other MDxx compounds. It was demonstrated by Miller, et al. (1997), that 5-(glutathion-S-yl)-alpha-methyldopamine and 5-(N-acetylcystein-S-yl)-alpha-methyldopamine produced similar effects to the parent compound, but did not induce neurotoxicity. Another related compound however, 2,5-bis-(glutathion-S-yl)-alpha-methyldopamine, 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 5-HT (Serotonin) axons.
Neurotoxin
A neurotoxin is a toxin that acts specifically on nerve cells , usually by interacting with membrane proteins such as ion channels. Some sources are more general, and define the effect of neurotoxins as occurring at nerve tissue...
and research chemical of the phenethylamine
Substituted phenethylamine
The substituted phenethylamines are chemical compounds with the 2-phenethylamine chemical structure modified at the phenyl ring, sidechain, and/or amino group. Some of them are psychoactive drugs, including stimulants, psychedelics, opioids, and entactogens, which exert their effects primarily...
and amphetamine
Substituted amphetamine
Substituted amphetamines are a chemical class of stimulants, entactogens, hallucinogens, and other drugs. They feature a phenethylamine core with a methyl group attached to the alpha carbon resulting in amphetamine, along with additional substitutions...
chemical classes. It is a metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
of various amphetamine derivatives such as amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
itself, methamphetamine
Methamphetamine
Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
, and MDMA ("Ecstasy"), MDA
MDA
-Companies, organizations and government bodies:* Maritime Domain Awareness, part of a U.S. Government interagency and international maritime security effort* MDA , formerly the Museum Documentation Association...
and has been suggested to play significant role in their neurotoxic effects on monoaminergic neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s. Further study has suggested that, alpha-methyldopamine itself is not directly responsible for the damaging effects, but a specific reaction between alpha-methyldopamine and one of the bodies endogenous antioxidants -glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
, may produce 2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine, which has been demonstrated in laboratory animals to cause the same neurotoxic effects seen by related stimulants and empathogens.
The basis of this idea is in the observation that MDA
MDA
-Companies, organizations and government bodies:* Maritime Domain Awareness, part of a U.S. Government interagency and international maritime security effort* MDA , formerly the Museum Documentation Association...
and MDMA may not themselves be responsible for their neurotoxicity, as an intracerebroventricular injection (injection directly into the brain itself) does not appear to cause neurotoxicity. While many studies cite excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
, or oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
as likely mechanisms, which may be an effect of the chemical itself, this has led to the search for other mechanisms for the observed toxicity of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
neurons and subsequent reduction in 5-HT (Serotonin) and 5-HIAA (its major metabolite in the body) in vivo following administration. A common theory follows that a metabolite in the periphery must be responsible, and several have been cited as responsible. Although, alpha-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 alpha-methyldopamine (α-MeDA) and 3-O-methyl-α-methyldopamine (3-O-Me-α-MeDA) did not produce neurotoxicity.
It was first demonstrated, in 1978, by Conway, et al. and possibly others that, while alpha-methyldopamine caused acute decreases in the levels of neuronal dopamine, in some areas of the brain in excess of 75%, levels returned to baseline within 12 hours, indicating that alpha-methyldopamine would not be responsible for the toxic effects observed.
However, the story complicates as alpha-methyldopamine readily oxidizes to the o-quinone
Quinone
A quinone is a class of organic compounds that are formally "derived from aromatic compounds [such as benzene or naphthalene] by conversion of an even number of –CH= groups into –C– groups with any necessary rearrangement of double bonds," resulting in "a fully conjugated cyclic dione structure."...
and reacts with endogenous antioxidants in the body, such as glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
(GSH). The mechanism of action behind amphetamines and their related compounds, causes the normally encapsulated neurotransmitters to be released from their oxidative vesicle within the neuron into the reductive environment of the cell cystol. This sudden release of oxidative molecules into the cell puts it under oxidative stress. As Glutathione is the major endogenous anti-oxidant produced in the body to protect against oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
and xenobiotics (foreign compounds), it likely plays at least some role in the neutralization of the suddenly released catecholamines (Dopamine and Norepinephrine), and Serotonin, as well as the breakdown of amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
, methamphetamine
Methamphetamine
Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
, MDA
MDA
-Companies, organizations and government bodies:* Maritime Domain Awareness, part of a U.S. Government interagency and international maritime security effort* MDA , formerly the Museum Documentation Association...
, MDMA, and other MDxx compounds. It was demonstrated by Miller, et al. (1997), that 5-(glutathion-S-yl)-alpha-methyldopamine and 5-(N-acetylcystein-S-yl)-alpha-methyldopamine produced similar effects to the parent compound, but did not induce neurotoxicity. Another related compound however, 2,5-bis-(glutathion-S-yl)-alpha-methyldopamine, 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 5-HT (Serotonin) axons.
See also
- α-Methylnorepinephrine
- α-Methyltyramine