DFMDA explained

Difluoromethylenedioxyamphetamine (DFMDA, 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] [3]

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.[4] 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,[5] [6] [7] making it unclear how much less neurotoxic DFMDA and related drugs would be in practice.

Notes and References

  1. Trachsel D, Hadorn M, Baumberger F . Synthesis of fluoro analogues of 3,4-(methylenedioxy)amphetamine (MDA) and its derivatives . Chemistry & Biodiversity . 3 . 3 . 326–36 . March 2006 . 17193269 . 10.1002/cbdv.200690035 . 10.1.1.688.5803 . 23036634 .
  2. Meanwell NA . Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design . Journal of Medicinal Chemistry . 54. 8. 2529–91. March 2011 . 21413808 . 10.1021/jm1013693 .
  3. Takač MJ, Magina JD, Takač T . Evaluation of phenylethylamine type entactogens and their metabolites relevant to ecotoxicology - a QSAR study . Acta Pharmaceutica . Zagreb, Croatia . 69 . 4 . 563–584 . December 2019 . 31639096 . 10.2478/acph-2019-0038 . 204850967 . free .
  4. Walline CC, Nichols DE, Carroll FI, Barker EL . 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 . 18354055 . 2637348 . 10.1124/jpet.108.136200 .
  5. Capela JP, Carmo H, Remião F, Bastos ML, Meisel A, Carvalho F . Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: an overview . Molecular Neurobiology . 39 . 3 . 210–71 . June 2009 . 19373443 . 10.1007/s12035-009-8064-1 . 10.1.1.670.6897 . 21190104 .
  6. Sarkar S, Schmued L . Neurotoxicity of ecstasy (MDMA): an overview . Current Pharmaceutical Biotechnology . 11 . 5 . 460–9 . August 2010 . 20420572 . 10.2174/138920110791591490.
  7. Escubedo E, Abad S, Torres I, Camarasa J, Pubill D . 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 . 21074589 . 10.1016/j.neuint.2010.11.001 . 2853533 .

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