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]
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
^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. doi:10.1002/cbdv.200690035. PMID17193269.
^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. PMID21413808.
^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. PMID513074.
^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. PMID2623014.
^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. doi:10.1007/s12035-009-8064-1. PMID19373443.
^Sarkar S, Schmued L (August 2010). "Neurotoxicity of ecstasy (MDMA): an overview". Current Pharmaceutical Biotechnology. 11 (5): 460–9. doi:10.2174/138920110791591490. PMID20420572.
^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. PMID21074589.
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