Next-Generation MDMA Analogue SDMA: Pharmacological and Metabolic Insights
Nina Kastner, Núria Nadal‐gratacós, Selina Hemmer, Letícia Alves Da Silva, J. M. T. Mckee, Tamara Hell, Giulia Cicalese, Marion Holy, Fatemeh Kooti, Kathrin Jäntsch, Ralf Baron, Naomi Shacham, Bruna Cuccurazzu, Adam L. Halberstadt, John D. Mccorvy, Thomas Stockner, Markus R. Meyer, Raúl López‐arnau, Matthias Grill, Harald H. Sitte
ACS Chemical Neuroscience December 2, 2025 DOI: 10.1021/acschemneuro.5c00782 via OpenAlex
Summary
AI-generated from the abstractReplacing the 1,3-benzodioxole group in MDMA (ecstasy) with a 1,3-benzoxathiole yields two analogues, SDA and SDMA, that interact with monoamine transporters similarly to MDMA but with key differences. SDA and SDMA inhibit dopamine and norepinephrine transporters more potently than MDMA and act as partial releasers at serotonin and dopamine transporters. Metabolism studies show SDA and SDMA are cleared faster, while MDMA and MDA degrade only weakly. In mice, SDMA does not produce rewarding effects, unlike MDMA, and SDA only shows a preference for the drug-paired compartment at the lowest dose. SDMA shares similar locomotor and hyperthermic profiles with MDMA, whereas SDA induces increased hyperlocomotion and more sustained hyperthermia. SDMA may be a safer candidate for further study.
Study at a glance
| Characteristics | In vitro and in vivo study Peer reviewed |
|---|---|
| Population | Human embryonic kidney (HEK293) cells and mice |
| Topics | MDMA Serotonin |
| Keywords | Norepinephrine transporter Monoamine neurotransmitter Dopamine transporter Reuptake inhibitor |
| Key finding | SDMA, an MDMA analogue with a 1,3-benzoxathiole substitution, shows enhanced metabolic clearance and reduced abuse potential in mice compared to MDMA. |
Abstract
3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, shows promise in treating depression and post-traumatic stress disorder (PTSD), resulting in breakthrough status. However, concerns regarding MDMA's abuse potential and cytotoxicity have sparked interest in developing safer analogues with similar therapeutic benefits. This study investigated the pharmacological properties of MDMA analogues in which the 1,3-benzodioxole group is replaced by a 1,3-benzoxathiole, termed SDA and SDMA, compared to MDA and MDMA through in silico, in vitro, and in vivo assays. In vitro experiments using human embryonic kidney (HEK293) cells examined the interactions with monoamine transporters. SDA and SDMA showed similar profiles to MDMA at the serotonin transporter (SERT), while both inhibited dopamine (DAT) and norepinephrine (NET) transporters more potently, in line with in silico molecular docking fitness scores of binding. SDA and SDMA also showed increased potency in evoking efflux through SERT and DAT acting as partial releasers. SDA and SDMA exhibited a similar interaction profile with 5-HT2 receptors compared with their respective analogues. Metabolism studies revealed faster clearance rates for SDA and SDMA, in contrast to MDA and MDMA, which exhibited only weak degradation. In contrast to MDMA's rewarding effects, SDMA did not induce significant effects in mice, while SDA only produced a significant preference for the drug-paired compartment at the lowest dose tested. Moreover, while SDMA shares similar locomotor and hyperthermic profiles as MDMA in mice, SDA induced increased hyperlocomotion and more sustained hyperthermia. In conclusion, these findings suggest that SDMA, with enhanced metabolic profiles and reduced abuse potential, is a promising candidate for further studies.