Next-Generation MDMA Analogue SDMA: Pharmacological and Metabolic Insights
Nina Kastner, Núria Nadal‐gratacós, Selina Hemmer, Leticia 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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro and in vivo study Peer reviewed |
|---|---|
| Population | Human embryonic kidney (HEK293) cells and mice |
| Interventions | SDA SDMA MDA MDMA |
| Topics | MDMA Serotonin |
| Keywords | Norepinephrine transporter Monoamine neurotransmitter Dopamine transporter Reuptake inhibitor Pharmacology Docking animal Potency 5-HT Receptor Conditioned place preference Serotonin transporter Antidepressant |
| Post-publication review | 3 comments on PubPeer (opens in new tab) · last active April 2026 |
| Key points | 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.