DiFMDA

Difluoromethylenedioxyamphetamine (DiFMDA) is a substituted derivative of 3,4-methylenedioxyamphetamine (MDA), which was developed by Daniel Trachsel and coworkers, along with the corresponding fluorinated derivatives of MDMA, MDEA, BDB and MBDB, with the aim of finding a non-neurotoxic drug able to be used as a less harmful substitute for entactogenic drugs 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 alpha-methyldopamine, it was hoped that the difluoromethylenedioxy bioisostere would show increased metabolic stability and less toxicity.[1][2]

DiFMDA
Clinical data
ATC code
  • none
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC10H11F2NO2
Molar mass215.200 g·mol−1
3D model (JSmol)
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These compounds have not yet been tested in animals to verify whether they show similar pharmacological activity to the non-fluorinated parent compounds, although in vitro binding studies show DFMDA to have a SERT affinity in between that of MDA and MDMA.[3] However, there is known to be a lack of bulk tolerance at this position of the molecule, shown by the generally reduced activity of the ethylidenedioxy and isopropylidenedioxy analogues.[4][5] It is also now generally accepted that MDMA neurotoxicity results from a variety of different causes and is not solely due to accumulation of alpha-methyldopamine,[6][7][8] making it unclear how much less neurotoxic DFMDA and related drugs would be in practice.

References
  1. Trachsel D, Hadorn M, Baumberger F (March 2006). "Synthesis of fluoro analogues of 3,4-(methylenedioxy)amphetamine (MDA) and its derivatives". Chemistry & Biodiversity. 3 (3): 326–36. CiteSeerX 10.1.1.688.5803. doi:10.1002/cbdv.200690035. PMID 17193269.
  2. Meanwell NA (March 2011). "Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design". Journal of Medicinal Chemistry. 54 (8): 2529–91. doi:10.1021/jm1013693. PMID 21413808.
  3. Walline CC, Nichols DE, Carroll FI, Barker EL (June 2008). "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. doi:10.1124/jpet.108.136200. PMC 2637348. PMID 18354055.
  4. Nichols DE, Kostuba LJ (October 1979). "Steric effects of substituents on phenethylamine hallucinogens. 3,4-(Methylenedioxy)amphetamine analogues alkylated on the dioxole ring". Journal of Medicinal Chemistry. 22 (10): 1264–7. doi:10.1021/jm00196a022. PMID 513074.
  5. Nichols DE, Oberlender R, Burris K, Hoffman AJ, Johnson MP (November 1989). "Studies of dioxole ring substituted 3,4-methylenedioxyamphetamine (MDA) analogues". Pharmacology Biochemistry and Behavior. 34 (3): 571–6. doi:10.1016/0091-3057(89)90560-1. PMID 2623014.
  6. Capela JP, Carmo H, Remião F, Bastos ML, Meisel A, Carvalho F (June 2009). "Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: an overview". Molecular Neurobiology. 39 (3): 210–71. CiteSeerX 10.1.1.670.6897. doi:10.1007/s12035-009-8064-1. PMID 19373443.
  7. Sarkar S, Schmued L (August 2010). "Neurotoxicity of ecstasy (MDMA): an overview". Current Pharmaceutical Biotechnology. 11 (5): 460–9. doi:10.2174/138920110791591490. PMID 20420572.
  8. Escubedo E, Abad S, Torres I, Camarasa J, Pubill D (January 2011). "Comparative neurochemical profile of 3,4-methylenedioxymethamphetamine and its metabolite alpha-methyldopamine on key targets of MDMA neurotoxicity". Neurochemistry International. 58 (1): 92–101. doi:10.1016/j.neuint.2010.11.001. PMID 21074589.
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