3,4-Dihydroxymethamphetamine

3,4-Dihydroxymethamphetamine
Clinical data
Other names	HHMA; 3,4-DHMA; Di-OH-MA; α-Methylepinine; α,N-Dimethyldopamine; α-Methyl-N-methyldopamine; 3,4-Dihydroxy-N-methylamphetamine
Identifiers
	IUPAC name 4-[2-(methylamino)propyl]benzene-1,2-diol;
CAS Number	15398-87-5;
PubChem CID	161126;
ChemSpider	141547;
UNII	VFV03WN1VN;
CompTox Dashboard (EPA)	DTXSID90934885 ;
Chemical and physical data
Formula	C10H15NO2
Molar mass	181.235 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC(CC1=CC(=C(C=C1)O)O)NC;
	InChI InChI=1S/C10H15NO2/c1-7(11-2)5-8-3-4-9(12)10(13)6-8/h3-4,6-7,11-13H,5H2,1-2H3; Key:NTCPGTZTPGFNOM-UHFFFAOYSA-N;

3,4-Dihydroxymethamphetamine (HHMA, 3,4-DHMA), or 3,4-dihydroxy-N-methylamphetamine, also known as α-methylepinine or α,N-dimethyldopamine, is the major metabolite of 3,4-methylenedioxy-N-methylamphetamine (MDMA).^[1]^[2]^[3] It is formed from MDMA by O-demethylation via cytochrome P450 enzymes including CYP2D6 as well as CYP1A2 and CYP3A4.^[1]^[3] Like MDMA, HHMA is a monoamine releasing agent.^[4]

Along with 3,4-dihydroxyamphetamine (HHA; α-methyldopamine), HHMA may be involved in the serotonergic neurotoxicity of MDMA.^[1]^[5]^[6]^[3] However, findings in this regard are conflicting, and the neurotoxicity of MDMA and related agents may instead be based on their mechanism of action without involvement of metabolites.^[3]^[5]^[6]^[7]^[8]

References

^ ^a ^b ^c Drevin G, Pena-Martin M, Bauduin A, Baudriller A, Briet M, Abbara C (August 2024). "Pharmacogenomics of 3,4-Methylenedioxymethamphetamine (MDMA): A Narrative Review of the Literature". Pharmaceutics. 16 (8): 1091. doi:10.3390/pharmaceutics16081091. PMC 11359928. PMID 39204437.
^ Dunlap LE, Andrews AM, Olson DE (October 2018). "Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine". ACS Chemical Neuroscience. 9 (10): 2408–2427. doi:10.1021/acschemneuro.8b00155. PMC 6197894. PMID 30001118.
^ ^a ^b ^c ^d Aguilar MA, García-Pardo MP, Parrott AC (January 2020). "Of mice and men on MDMA: A translational comparison of the neuropsychobiological effects of 3,4-methylenedioxymethamphetamine ('Ecstasy')". Brain Research. 1727: 146556. doi:10.1016/j.brainres.2019.146556. PMID 31734398. The metabolites of MDMA are 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), α-methyldopamine (α-MeDA), N-methyl-αmethyldopamine (N-Me-α-MeDA) and 5-(glutathion-S-yl)-α-methyldopamine [5-(GSH)-α-MeDA]. There is a substantial hepatic metabolism of MDMA, since levels of MDA and HMMA exceed that of MDMA in plasma. [...] The metabolites of MDMA, as well as those of DA, enhance the formation of quinoproteins and alter synaptosomal glutathione status, suggesting the role of these metabolites in the neurotoxicity induced by MDMA (Barbosa et al., 2012). However, the major reactive metabolite of MDMA, HHMA, does not contribute to acute or long-term MDMA-induced DA depletion, since peripheral administration of this metabolite fails to alter striatal DA. Furthermore, HHMA has been detected in the brain following its systemic injection, but not after systemic MDMA administration (Escobedo et al., 2005).
^ 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 [...]
^ ^a ^b Seiden LS, Sabol KE (1996). "Methamphetamine and Methylenedioxymethamphetamine Neurotoxicity: Possible Mechanisms of Cell Destruction". In Majewska MD (ed.). Neurotoxicity and Neuropathology Associated with Cocaine Abuse. NIDA research monograph. U.S. Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse. pp. 251–276. Retrieved 30 September 2024. Steele and colleagues (1991) found that alpha-methylepinine, a metabolite of MDMA formed by demethylenation, failed to damage the 5-HT system in rats.
^ ^a ^b Schmitt KC, Reith ME (February 2010). "Regulation of the dopamine transporter: aspects relevant to psychostimulant drugs of abuse". Annals of the New York Academy of Sciences. 1187: 316–340. doi:10.1111/j.1749-6632.2009.05148.x. PMID 20201860. In humans, MDA and MDMA are largely metabolized via demethylenation by the hepatic CYP2D6 enzyme to the respective 3,4-dihydroxyamphetamine species (α-methyldopamine and α,N-dimethyldopamine).135 In recent years, several investigators have revealed that—much like dopamine—these catechol species readily undergo oxidation to semiquinone and quinone species that can form neurotoxic thioether compounds in vivo.136,137 [...] In particular, the dopaminoquinone-like metabolite of MDA/MDMA can undergo conjugation with the cysteinyl thiol moiety of the endogenous reductant glutathione (GSH) to form the thioether 5-(glutathionyl)-α-methyldopamine (5-(GSH)-αMeDA) or its N-methyl analogue.136 In the central nervous system, the 5-(glutathionyl)-thioethers are ultimately metabolized via the mercapturic acid pathway to form 5-(N-acetyl-cysteinyl)-α-methyldopamine (5-(NAC)-αMeDA) and its N-methyl analogue (5-(NAC)-α,N-diMeDA). The structural formulae of these metabolites and their relative potencies as neurotoxins are displayed in Figure 2. The thioether metabolites are potent serotonergic neurotoxins that can induce a dose-dependent increase in ROS formation and cause caspase-3–mediated apoptosis in cultured cortical neurons.137 Moreover, direct intrastriatal administration of pure 5-(NAC)-α,N-diMeDA in rats fully recapitulates the serotonergic toxicity observed with systemic high-dose MDMA.136 These thioethers are detectable in the rat brain after systemic administration of a high-dose neurotoxic regimen of MDMA—repeated dosing leads to significant accumulation due to a nonlinear increase in elimination half-life.139
^ Baggott M, Mendelson J (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.
^ 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.

[DrevinPena-MartinBauduin2024-1] Drevin G, Pena-Martin M, Bauduin A, Baudriller A, Briet M, Abbara C (August 2024). "Pharmacogenomics of 3,4-Methylenedioxymethamphetamine (MDMA): A Narrative Review of the Literature". Pharmaceutics. 16 (8): 1091. doi:10.3390/pharmaceutics16081091. PMC 11359928. PMID 39204437.

[DunlapAndrewsOlson2018-2] Dunlap LE, Andrews AM, Olson DE (October 2018). "Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine". ACS Chemical Neuroscience. 9 (10): 2408–2427. doi:10.1021/acschemneuro.8b00155. PMC 6197894. PMID 30001118.

[AguilarGarcía-PardoParrott2020-3] Aguilar MA, García-Pardo MP, Parrott AC (January 2020). "Of mice and men on MDMA: A translational comparison of the neuropsychobiological effects of 3,4-methylenedioxymethamphetamine ('Ecstasy')". Brain Research. 1727: 146556. doi:10.1016/j.brainres.2019.146556. PMID 31734398. The metabolites of MDMA are 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), α-methyldopamine (α-MeDA), N-methyl-αmethyldopamine (N-Me-α-MeDA) and 5-(glutathion-S-yl)-α-methyldopamine [5-(GSH)-α-MeDA]. There is a substantial hepatic metabolism of MDMA, since levels of MDA and HMMA exceed that of MDMA in plasma. [...] The metabolites of MDMA, as well as those of DA, enhance the formation of quinoproteins and alter synaptosomal glutathione status, suggesting the role of these metabolites in the neurotoxicity induced by MDMA (Barbosa et al., 2012). However, the major reactive metabolite of MDMA, HHMA, does not contribute to acute or long-term MDMA-induced DA depletion, since peripheral administration of this metabolite fails to alter striatal DA. Furthermore, HHMA has been detected in the brain following its systemic injection, but not after systemic MDMA administration (Escobedo et al., 2005).

[Blough2008-4] 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 [...]

[SeidenSabol1996-5] Seiden LS, Sabol KE (1996). "Methamphetamine and Methylenedioxymethamphetamine Neurotoxicity: Possible Mechanisms of Cell Destruction". In Majewska MD (ed.). Neurotoxicity and Neuropathology Associated with Cocaine Abuse. NIDA research monograph. U.S. Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse. pp. 251–276. Retrieved 30 September 2024. Steele and colleagues (1991) found that alpha-methylepinine, a metabolite of MDMA formed by demethylenation, failed to damage the 5-HT system in rats.

[SchmittReith2010-6] Schmitt KC, Reith ME (February 2010). "Regulation of the dopamine transporter: aspects relevant to psychostimulant drugs of abuse". Annals of the New York Academy of Sciences. 1187: 316–340. doi:10.1111/j.1749-6632.2009.05148.x. PMID 20201860. In humans, MDA and MDMA are largely metabolized via demethylenation by the hepatic CYP2D6 enzyme to the respective 3,4-dihydroxyamphetamine species (α-methyldopamine and α,N-dimethyldopamine).135 In recent years, several investigators have revealed that—much like dopamine—these catechol species readily undergo oxidation to semiquinone and quinone species that can form neurotoxic thioether compounds in vivo.136,137 [...] In particular, the dopaminoquinone-like metabolite of MDA/MDMA can undergo conjugation with the cysteinyl thiol moiety of the endogenous reductant glutathione (GSH) to form the thioether 5-(glutathionyl)-α-methyldopamine (5-(GSH)-αMeDA) or its N-methyl analogue.136 In the central nervous system, the 5-(glutathionyl)-thioethers are ultimately metabolized via the mercapturic acid pathway to form 5-(N-acetyl-cysteinyl)-α-methyldopamine (5-(NAC)-αMeDA) and its N-methyl analogue (5-(NAC)-α,N-diMeDA). The structural formulae of these metabolites and their relative potencies as neurotoxins are displayed in Figure 2. The thioether metabolites are potent serotonergic neurotoxins that can induce a dose-dependent increase in ROS formation and cause caspase-3–mediated apoptosis in cultured cortical neurons.137 Moreover, direct intrastriatal administration of pure 5-(NAC)-α,N-diMeDA in rats fully recapitulates the serotonergic toxicity observed with systemic high-dose MDMA.136 These thioethers are detectable in the rat brain after systemic administration of a high-dose neurotoxic regimen of MDMA—repeated dosing leads to significant accumulation due to a nonlinear increase in elimination half-life.139

[BaggottMendelson2001-7] Baggott M, Mendelson J (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.

[SpragueEvermanNichols1998-8] 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.

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3,4-Dihydroxymethamphetamine

See also

References