Chemistry:DFMDA
DFMDA, also known as F2-MDA or as 3,4-(difluoromethylenedioxy)amphetamine, is a chemical compound of the phenethylamine, amphetamine, and MDxx families related to the entactogen and psychedelic drug MDA.[1][2][3] It is the derivative of MDA in which the two hydrogen atoms on the carbon atom of the 3,4-methylenedioxy ring have been replaced with fluorine atoms.[1][2][3]
Daniel Trachsel tested DFMDA in humans and found that it was inactive at doses of up to 250 mg orally.[3][1] Higher doses were not tested.[3][1] For comparison, he listed MDA's dose as 80 to 160 mg orally.[3]
DFMDA was active at the serotonin transporter (SERT) similarly to MDA and MDMA and with intermediate affinity between the two.[3][1]
It was developed with the aim of finding a non-neurotoxic drug able to be used as a less harmful substitute for entactogens such as MDMA. Since a major route of the normal metabolism of these compounds is scission of the methylenedioxy ring, producing neurotoxic metabolites such as α-methyldopamine, it was hoped that the difluoromethylenedioxy bioisostere would show increased metabolic stability and less toxicity.[2][4][5] These compounds have not yet been tested in animals to verify whether they show similar pharmacological activity to the non-fluorinated parent compounds.[6] It is also now generally accepted that MDMA neurotoxicity results from a variety of different causes and is not solely due to accumulation of α-methyldopamine,[7][8][9] making it unclear how much less neurotoxic DFMDA and related drugs would be in practice.
The chemical synthesis of DFMDA has been described.[2] Some notable analogues of DFMDA include DFMDMA (F2-MDMA), EIDA, and IDA, among others.[3][1] Other fluorinated MDxx derivatives, for instance derivatives of MDEA, BDB, and MBDB, have also been described.[2][1]
DFMDA was first described in the scientific literature by Daniel Trachsel and colleagues in 2006.[2] He described its properties and effects in humans in 2012 and 2013.[3][1]
See also
- Substituted methylenedioxyphenethylamine
- d2-MDMA
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Trachsel, D.; Lehmann, D.; Enzensperger, C. (2013) (in de). Phenethylamine: von der Struktur zur Funktion. Nachtschatten-Science (1 ed.). Solothurn: Nachtschatten-Verlag. ISBN 978-3-03788-700-4. OCLC 858805226. https://books.google.com/books?id=-Us1kgEACAAJ.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Synthesis of fluoro analogues of 3,4-(methylenedioxy)amphetamine (MDA) and its derivatives". Chem Biodivers 3 (3): 326–336. March 2006. doi:10.1002/cbdv.200690035. PMID 17193269. https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=820d672ead44ebea16bdd50b67b74393b4d0c8d4.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 "Fluorine in psychedelic phenethylamines". Drug Test Anal 4 (7–8): 577–590. 2012. doi:10.1002/dta.413. PMID 22374819. https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=c7b41be36b1f580a264a752521d151e6e2d9409d. "The first fluorinated 3,4-methylenedioxyphenethylamines described in the scientific literature were compounds 90–95, all bearing a 3,4-(difluoromethylenedioxy) moiety (Figure 6, B).[96] It was hoped that this introduction of fluorine could lower the formation of potentially neurotoxic metabolites of MDMA[96] by either blocking formation of neurotoxic a-methyldopamines via increased methylene bridge stability or formation of glutathione adducts via changing the electron density of the aromatic nucleus. Only few pharmacological characterizations have been carried out so far. Initial in vitro investigations showed DFMDA (91: Ki = 1200nM) to have a SERT affinity between that of MDA (3: Ki = 700nM) and MDMA (4: Ki = 1600nM) using a functional assay.[104] DFMDA (91) did not appear to show any activity in humans up to 250 mg, whereas MDA (3) showed its full activity at a dose of 80–160 mg.[3] The difluoro analog DFMDMA (92) was inactive at levels up to 120 mg (MDMA, 4: 80–150 mg[3]). [...] Fluorine introduction was also performed with the 3,4-methylenedioxyphenethylamines and a total of nine derivatives (90–98) were described. Monoamine transporter binding properties described so far did not elucidate the extent to which these compounds show similar neuropharmacological mechanisms of action in comparison to MDMA (4). Further work would also be required to shed more light on the impact of fluorination on the formation of potential neurotoxins.[93,95,96] What has been found so far is that human activity of DFMDA (91, >250 mg) or DFMDMA (92, >120 mg) appears to be absent which reveals that the significant properties responsible for the unique action of MDMA (4) have been changed by fluorine introduction into the 3,4-methylenedioxy bridge.".
- ↑ "Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design". Journal of Medicinal Chemistry 54 (8): 2529–91. March 2011. doi:10.1021/jm1013693. PMID 21413808.
- ↑ "Evaluation of phenylethylamine type entactogens and their metabolites relevant to ecotoxicology - a QSAR study". Acta Pharmaceutica (Zagreb, Croatia) 69 (4): 563–584. December 2019. doi:10.2478/acph-2019-0038. PMID 31639096.
- ↑ "Comparative molecular field analysis using selectivity fields reveals residues in the third transmembrane helix of the serotonin transporter associated with substrate and antagonist recognition". The Journal of Pharmacology and Experimental Therapeutics 325 (3): 791–800. June 2008. doi:10.1124/jpet.108.136200. PMID 18354055.
- ↑ "Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: an overview". Molecular Neurobiology 39 (3): 210–71. June 2009. doi:10.1007/s12035-009-8064-1. PMID 19373443.
- ↑ "Neurotoxicity of ecstasy (MDMA): an overview". Current Pharmaceutical Biotechnology 11 (5): 460–9. August 2010. doi:10.2174/138920110791591490. PMID 20420572.
- ↑ "Comparative neurochemical profile of 3,4-methylenedioxymethamphetamine and its metabolite alpha-methyldopamine on key targets of MDMA neurotoxicity". Neurochemistry International 58 (1): 92–101. January 2011. doi:10.1016/j.neuint.2010.11.001. PMID 21074589.
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