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.2025 Dec 17;16(24):4725-4740.
doi: 10.1021/acschemneuro.5c00782. Epub 2025 Dec 2.

Next-Generation MDMA Analogue SDMA: Pharmacological and Metabolic Insights

Affiliations

Next-Generation MDMA Analogue SDMA: Pharmacological and Metabolic Insights

Nina Kastner et al. ACS Chem Neurosci..

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 throughin silico,in vitro, andin 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 within 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.

Keywords: MDMA; analogues; hepatic metabolism; monoamine receptors; monoamine transporters; pharmacological profile.

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Figures

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(A) Structures of MDA, MDMA, SDA, and SDMA. Uptake inhibition assaysof substances at (B) SERT, (C) DAT, and (D) NET. Curves were fittedwith a sigmoidal dose–response curve to obtain half-maximalinhibitory concentration (IC50) values (see Table ). Transporter-mediated effluxof (E) SERT, (F) DAT, and (G) NET in a concentration dependent matterof the compound of interest is fitted with a sigmoidal dose–responsecurve to obtain half maximal effective concentration (EC50) values (see Table ). Individual data points are represented with mean ± standarddeviation (SD) from three to five independent experiments, each performedin triplicate. Effects of MDA, MDMA, SDA, and SDMA on 5-HT2 receptor activity measured using a Gq dissociation BRET-based assay:(h) 5-HT2A, (i) 5-HT2B, and (j) 5-HT2C. 5-HT was used as positive control, and data are represented asmean ± SEM from three to four independent cell culture preparations(n = 3–4).
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Top-1 docking poses of MDA, MDMA, SDA, and SDMA in SERT, DAT, andNET proteins. The first row depicts the superposition of all compounds’top-1 binding poses with the cognate substrate in each protein’sorthosteric binding pocket (S1). In the following rows, the compoundsare shown individually in superposition with their cognates. The dashedcircles represent functional groups of the cognate that are mimickedin the compound structure. Hydrogen atoms are not displayed. Fitnessscore values for the best pose in each cluster are presented in thetable underneath.
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Top-1 docking poses for MDA, MDMA, SDA, and SDMA in SERT,DAT,and NET proteins. The first row represents the superposition of allcompounds’ top-1 binding poses with the cognate substrate ineach protein’s orthosteric binding pocket (S1). The 2D interactionscheme for each cognate and compound, obtained using Maestro version13.6.122, is shown in the rows below with the main interactions withthe respective protein highlighted. Asterisks indicate residues thatdo not appear in interaction with the cognate.
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Metabolic pathways of (A) SDMA and (B) SDA in incubations withpooled human liver microsomes and/or the S9 fraction. Metabolite-IDscorrespond to Table . Metabolic stability of (C) MDA, (D) SDA, and (E) SDMA in incubationswith pooled human liver microsomes (pHLM). Data of MDMA was publishedpreviously. Incubation time is plottedversus the natural logarithm of the peak area of the compound. Pointsindicate mean values (n = 2),t1/2 = in vitro half-life. M = Metabolite-ID.
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Effects of increasingdoses of SDA (A) and SDMA (D) and comparativeeffects of MDMA, SDA, and SDMA at 10 mg/kg (G) on cumulative horizontallocomotor activity in mice. Data is presented as mean ± SD ofthe total distance (cm) traveled in 120 min and was analyzed withDunn’s multiple-comparisons test: *p <0.05 and ***p < 0.001 vs saline, ##p < 0.01 and ###p < 0.001 vs 2.5 mg/kg, @@@p < 0.001 vs MDMA, and +++p < 0.001vs SDA.N = 12–14 per group. (B, E, H) Openfield test (thigmotaxis) in male Swiss CD-1 mice. Bars represent mean± SD of time in the center (s). Dunn’s/Tukey’smultiple-comparisons test: **p < 0.01 vs salineand ##p < 0.01 vs 2.5 mg/kg.N = 12–14/group. (C, F, I) Conditioned place preference testin mice. Data is presented as mean ± SD of the preference score(difference between the time spent in the drug-paired compartmenton the test day and the preconditioning day).N =10–14 per group. Dunn’s multiple-comparisons test: *p < 0.05 vs saline. (J, K) Core body temperature changesin mice at 22 ± 1 °C (J) and 28 ± 1 °C (K). Datais normalized to the baseline temperature of each respective animal,presented as mean ± SD of the increase in core body temperaturefor each time point and analyzed using Tukey’s multiple comparisonstest (n = 5–7 per group) | *p < 0.05 vs saline, **p < 0.01 vs saline,***p < 0.001 vs saline, @p <0.05 vs MDMA, @@p < 0.01 vs MDMA, +p < 0.05 vs SDA, ++p < 0.01 vs SDA. For panelsH–I, the saline group is composed of pooled saline controlsfrom panels B, E and C, F, respectively. Doses were calculated basedon the free base form of each compound.
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