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

research chemical Research chemicals are chemical substances used by scientists 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 o ...

of the

catecholamine A catecholamine (; abbreviated CA) 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. Catechol can be either a free molecule or a subst ...

and

amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...

chemical class Chemical classification systems attempt to classify elements or compounds according to certain chemical functional or structural properties. Whereas the structural properties are largely intrinsic, functional properties and the derived classificat ...

es. Its bis- glutathionyl metabolite 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 – specificall ...

when directly injected into the brain's ventricles. Interest lies in the fact that

MDA MDA, mda, or ''variation'', may refer to: Places * Moldova, a country in Europe with the ISO 3166-1 country code MDA Politics * Meghalaya Democratic Alliance (2018), ruling coalition government in the Indian State of Meghalaya led by National Pe ...

and

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in Tablet (pharmacy), tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for Recreational dru ...

may not themselves be responsible for their neurotoxicity, as an intracerebroventricular injection does not appear to cause neurotoxicity. While many studies suggest

excitotoxicity In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate re ...

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

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 () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

axons 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-Me-DA or HHA) 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 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 could not be responsible for the toxic effects observed. However, the story complicates as alpha-methyldopamine readily oxidizes to the o-

quinone The quinones are a class of organic compounds that are formally "derived from aromatic compounds

uch as benzene or naphthalene Uch ( pa, ; ur, ), frequently referred to as Uch Sharīf ( pa, ; ur, ; ''"Noble Uch"''), is a historic city in the southern part of Pakistan's Punjab province. Uch may have been founded as Alexandria on the Indus, a town founded by Alexand ...

by conversion of an even number of –CH= groups into –C(=O)– groups with any necessary rearrangement of double ...

and reacts with endogenous antioxidants in the body, such as

glutathione Glutathione (GSH, ) 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 such as reactive oxygen species, free radicals, pero ...

(GSH). 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 when injected intracerebroventricularly. However the derivative metabolite 2,5-bis-(glutathion-S-yl)-alpha-methyldopamine (injected at ≈1.5x 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 5-HT (Serotonin) axons.

References

{{DEFAULTSORT:Methyldopamine, alpha- Substituted amphetamines Catecholamines Neurotoxins

See also

References