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. It is a monoamine releasing agent^[1] and a metabolite of MDMA and MDA.^[2] The bis-glutathionyl metabolite of α-methyldopamine is slightly neurotoxic when directly injected into the brain's ventricles.^[2]

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
(verify)

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.^[3]

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.^[4]

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.^[5]

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, specifically simultaneous induction of serotonin and dopamine release.^[6][7] 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 1 hour do result in signs of neurotoxicity.^[6]

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 (HHMA; α-methylepinine)
• 4-Hydroxy-3-methoxyamphetamine (HMA)
• 4-Hydroxy-3-methoxymethamphetamine (HMMA)
• 2,4,5-Trihydroxyamphetamine (THA)
• 2,4,5-Trihydroxymethamphetamine (THMA)

References

1. Blough B (July 2008). "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN 978-0-470-11790-3. Archived from the original on 4 November 2024. TABLE 11-2 Comparison of the DAT- and NET-Releasing Activity of a Series of Amphetamines [...]
2. Monks TJ, Jones DC, Bai F, Lau SS (April 2004). "The role of metabolism in 3,4-(+)-methylenedioxyamphetamine and 3,4-(+)-methylenedioxymethamphetamine (ecstasy) toxicity". Ther Drug Monit. 26 (2): 132–136. doi:10.1097/00007691-200404000-00008. PMID 15228153.
3. McCann UD, Ricaurte GA (April 1991). "Major metabolites of (+/-)3,4-methylenedioxyamphetamine (MDA) do not mediate its toxic effects on brain serotonin neurons". Brain Research. 545 (1–2): 279–282. doi:10.1016/0006-8993(91)91297-E. PMID 1860050. S2CID 2574803.
4. Conway EL, Louis WJ, Jarrott B (December 1978). "Acute and chronic administration of alpha-methyldopa: regional levels of endogenous and alpha-methylated catecholamines in rat brain". European Journal of Pharmacology. 52 (3–4): 271–280. doi:10.1016/0014-2999(78)90279-0. PMID 729639.
5. Miller RT, Lau SS, Monks TJ (April 1997). "2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine, a putative metabolite of (+/-)-3,4-methylenedioxyamphetamine, decreases brain serotonin concentrations". European Journal of Pharmacology. 323 (2–3): 173–180. doi:10.1016/S0014-2999(97)00044-7. PMID 9128836.
6. Baggott, Matthew; Mendelson, John (2001). "Does MDMA Cause Brain Damage?". In Holland, J. (ed.). Ecstasy: The Complete Guide: A Comprehensive Look at the Risks and Benefits of MDMA. Inner Traditions/Bear. pp. 110–145, 396–404. ISBN 978-0-89281-857-0. Retrieved 24 November 2024. While a single injection of MDMA into the brain (intracerebroventricularly) had no effect on TPH activity, slow infusion of 1 mg/kg MDMA into the brain over 1 hr produced enough oxidative stress to acutely reduce TPH activity (Schmidt and Taylor 1988). The acute decrease in TPH activity is an early effect of MDMA and can be measured at post 15 min (Stone et al. 1989b). TPH inactivation can also be produced by non-neurotoxic MDMA doses (Schmidt and Taylor 1988; Stone et al. 1989a; Stone et al. 1989b). It therefore appears that MDMA rapidly induces oxidative stress but only produces neurotoxicity when endogenous free radical scavenging systems are overwhelmed.
7. Sprague JE, Everman SL, Nichols DE (June 1998). "An integrated hypothesis for the serotonergic axonal loss induced by 3,4-methylenedioxymethamphetamine" (PDF). Neurotoxicology. 19 (3): 427–441. PMID 9621349.