Faculty Collaboration Database

Next-Generation MDMA Analogue SDMA: Pharmacological and Metabolic Insights. ACS Chem Neurosci 2025 Dec 17;16(24):4725-4740

Date

12/02/2025

Pubmed ID

41329099

Pubmed Central ID

PMC12715756

DOI

10.1021/acschemneuro.5c00782

Scopus ID

2-s2.0-105024898462 (requires institutional sign-in at Scopus site)

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.

Author List

Kastner N, Nadal-Gratacós N, Hemmer S, Alves da Silva L, McKee JL, Hell T, Cicalese G, Holy M, Kooti F, Jäntsch K, Baron R, Shacham N, Cuccurazzu B, Halberstadt AL, McCorvy JD, Stockner T, Meyer MR, López-Arnau R, Grill M, Sitte HH

Author

John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Dopamine Plasma Membrane Transport Proteins
HEK293 Cells
Hallucinogens
Humans
Male
Mice
Mice, Inbred C57BL
Molecular Docking Simulation
N-Methyl-3,4-methylenedioxyamphetamine
Norepinephrine Plasma Membrane Transport Proteins
Serotonin Plasma Membrane Transport Proteins