α-Methyldopamine

α-Methyldopamine (α-Me-DA), also known as 3,4-dihydroxyamphetamine (3,4-DHA or HHA) or as catecholamphetamine, is a research chemical of the catecholamine and amphetamine families. Its bis-glutathionyl metabolite is slightly neurotoxic when directly injected into the brain's ventricles.

α-Methyldopamine

Clinical data
Other names	α-Me-DA; 3,4-Dihydroxyamphetamine; 3,4-DHA; HHA; 3,4-Dihydroxy-α-methylphenethylamine; 3,4-Dihydroxy-α-methyl-β-phenylethylamine; Methyldopamine; Catecholamphetamine
ATC code	None
Identifiers
IUPAC name 4-(2-aminopropyl)benzene-1,2-diol
CAS Number	555-64-6 Y
PubChem CID	17005
ChemSpider	16110 Y
UNII	XQ9A7WCY2L
ChEBI	CHEBI:193722
ChEMBL	ChEMBL28278 Y
CompTox Dashboard (EPA)	DTXSID00897235
Chemical and physical data
Formula	C9H13NO2
Molar mass	167.208 g·mol−1
3D model (JSmol)	Interactive image
SMILES Oc1ccc(cc1O)CC(N)C
InChI InChI=1S/C9H13NO2/c1-6(10)4-7-2-3-8(11)9(12)5-7/h2-3,5-6,11-12H,4,10H2,1H3 Y Key:KSRGADMGIRTXAF-UHFFFAOYSA-N Y
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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, as an intracerebroventricular injection does not appear to cause neurotoxicity. While many studies suggest excitotoxicity or oxidative stress 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 axons and subsequent reduction in serotonin (5-HT) and 5-HIAA (its major metabolite in the body) in vivo following administration. A common theory follows that a metabolite 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 neuronal dopamine, in some areas of the brain in excess of 75%, levels returned to baseline within 12 hours, 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 and reacts with endogenous antioxidants in the body, such as glutathione (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 ~1.5 times 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 axons.

Chemistry

α-Methyldopamine, also known as 3,4-dihydroxy-α-methylphenethylamine or as 3,4-dihydroxyamphetamine, is a substituted phenethylamine, catecholamine, and amphetamine derivative. It is the α-methylated or amphetamine analogue of dopamine (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 (norpholedrine; α-methyltyramine; 4-hydroxyamphetamine)

See also

• 3,4-Dihydroxymethamphetamine (α-methylepinine; α,N-dimethyldopamine)