Synthesis of Fluoro Analogues of 3,4‐(Methylenedioxy)amphetamine (MDA) and Its Derivatives

Abstract

The role of the metabolism of the entactogen 3,4-(methylenedioxy)methamphetamine (MDMA; 1b) in neurotoxic or psychopharmacologic action is widely discussed, but not yet fully understood. To prompt further investigation into the role of MDMA metabolism, six new 3,4-(difluoromethylenedioxy) analogues of MDMA (1b) were prepared and characterized. Although electronically very different, the fluoro analogues 3-5 should be sterically very similar to the non-fluorinated parent compounds. The F-atoms may prevent the formation of toxic metabolites produced via a radical pathway (Scheme 1). Different theories regarding MDMA-induced neurotoxicity are briefly reviewed and discussed. The novel compounds 3-5 may help to verify the hypothesis that MDMA-induced neurotoxicity is the result of the formation of metabolites lacking the methylenedioxy bridge.

Fluorine in psychedelic phenethylamines

“…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). [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. [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.…”

“…As an entactogen MDMA (4) differs from stimulants and psychedelics not only mechanistically but also in its psychological effects. [5,[92][93][94][95][96] In contrast to the psychedelic phenethylamines, MDMA acts via monoamine transporters and not as a 5-HT receptor agonist. [3,54] Its unique pharmacological properties also made it attractive for psychotherapy, and currently there are clinical trials which investigate MDMA (4) assisted psychotherapy in patients with posttraumatic stress disorders (PTSD) and anxiety associated with terminal cancer.…”

“…Briefly, MDMA (4) is known to release serotonin (5-HT) and, to a lesser extent dopamine (DA) as well as norepinephrine (NE). [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. [98][99][100] It also increases 5-HT levels by inhibiting the serotonin transporter (SERT).…”

“…Fluorine introduction was also performed with the 3,4-methylenedioxyphenethylamines and a total of nine derivatives (90)(91)(92)(93)(94)(95)(96)(97)(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).…”

Evaluation of phenylethylamine type entactogens and their metabolites relevant to ecotoxicology – a QSAR study

“…propan-2-amine (DiFMDA, 23) in which the 2,2-disubstitution enhanced the metabolic stability of this drug (50). For this metabolic reaction the main cytochrome P450 enzymes, i.e., CYP1A2 and 2D6 were predicted with the highest probability, however, CYP2C9, 2C19 and 3A4 were also predicted, but to significantly less extent (Table S-…”