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.2024 Sep;168(9):2022-2042.
doi: 10.1111/jnc.16149. Epub 2024 Jun 19.

Bioisosteric analogs of MDMA: Improving the pharmacological profile?

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Bioisosteric analogs of MDMA: Improving the pharmacological profile?

Ana Sofia Alberto-Silva et al. J Neurochem.2024 Sep.

Abstract

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') is re-emerging in clinical settings as a candidate for the treatment of specific neuropsychiatric disorders (e.g. post-traumatic stress disorder) in combination with psychotherapy. MDMA is a psychoactive drug, typically regarded as an empathogen or entactogen, which leads to transporter-mediated monoamine release. Despite its therapeutic potential, MDMA can induce dose-, individual-, and context-dependent untoward effects outside safe settings. In this study, we investigated whether three new methylenedioxy bioisosteres of MDMA improve its off-target profile. In vitro methods included radiotracer assays, transporter electrophysiology, bioluminescence resonance energy transfer and fluorescence-based assays, pooled human liver microsome/S9 fraction incubations, metabolic stability studies, isozyme mapping, and liquid chromatography coupled to high-resolution mass spectrometry. In silico methods included molecular docking. Compared with MDMA, all three MDMA bioisosteres (ODMA, TDMA, and SeDMA) showed similar pharmacological activity at human serotonin, dopamine, and norepinephrine transporters (hSERT, hDAT, and hNET, respectively) but decreased agonist activity at 5-HT2A/2B/2C receptors. Regarding their hepatic metabolism, they differed from MDMA, with N-demethylation being the only metabolic route shared, and without forming phase II metabolites. In addition, TDMA showed an enhanced intrinsic clearance in comparison to its congeners. Additional screening for their interaction with human organic cation transporters (hOCTs) and plasma membrane monoamine transporter (hPMAT) revealed a weaker interaction of the MDMA analogs with hOCT1, hOCT2, and hPMAT. Our findings suggest that these new MDMA bioisosteres might constitute appealing therapeutic alternatives to MDMA, sparing the primary pharmacological activity at hSERT, hDAT, and hNET, but displaying a reduced activity at 5-HT2A/2B/2C receptors and alternative hepatic metabolism. Whether these MDMA bioisosteres may pose lower risk alternatives to the clinically re-emerging MDMA warrants further studies.

© 2024 The Author(s). Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.

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Conflict of interest statement

Declaration of Competing Interest

The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
3,4-Methylenedioxymethamphetamine (MDMA) and its analogs 1-(2,1,3-benzoxadiazol-5-yl)-N-methylpropan-2-amine (ODMA), 1-(2,1,3-benzothiadiazol-5-yl)-N-methylpropan-2-amine (TDMA), and 1-(2,1,3-benzoselenadiazol-5-yl)-N-methylpropan-2-amine (SeDMA) interact at low micromolar concentrations with the monoamine transporters. (a) Chemical structures of (±) MDMA and its analogs (±) ODMA, (±) TDMA, and (±) SeDMA, in which the methylenedioxy group or its chemical modification is highlighted in red, blue, purple, or green, respectively. (b) Uptake inhibition curves at human serotonin transporter (hSERT) (left panel), human dopamine transporter (hDAT) (middle panel), and human norepinephrine transporter (hNET) (right panel). Data are mean ± standard deviation (SD) from three to five independent cell culture preparations (n=3–5), performed in triplicate. Curves were plotted and fitted by non-linear regression, and data were best fitted to a sigmoidal dose-response curve to obtain half-maximal inhibitory concentration (IC50) values (see Table 1). (c) Transporter-mediated release of preloaded [3H]substrate from human embryonic kidney 293 (HEK293) cells stably expressing hSERT, hDAT, or hNET. Compounds were added from 8 to 18 min at a concentration close to their IC50 value, either in vehicle (KHB) (empty symbols) or in monensin (10 μM) (MON) (filled symbols); data are mean ± SD from four to five independent cell culture preparations (n=4–5) performed in duplicate (batch release assays (hSERT) or in triplicate (superfusion release assays (hDAT and hNET)). A statistical analysis with a mixed-effects model employing Šidák correction for multiple comparisons confirmed significant differences between KHB and MON conditions at the indicated time points, thus validating the releasing capabilities of the compounds. For control experiments with known full releasing agents or inhibitors at each transporter, see Figure S1. Statistical significance was defined at ap value lower than 0.05. *denotesp<0.05, **p<0.01, and ***p<0.001 (from left to right:p values for hSERT – MDMA:p = <0.0001, <0.0001, <0.0001, 0.0007, respectively, df = 13–17; ODMA:p = <0.0001 (all), df = 13–17; TDMA:p = 0.001, <0.0001, <0.0001, 0.0001, 0.0037, df = 11–14; SeDMA:p = <0.0001, <0.0001, <0.0001, 0.0006, 0.0048, df = 7–12;p values for hDAT – MDMA:p = <0.0001 (all), df = 19–22; ODMA:p = 0.0067, 0.0104, 0.0132, 0.0139, df = 17–19; TDMA:p = 0.0044, 0.0015, 0.0035, 0.0011, 0.0063, df = 14–19; SeDMA:p = <0.0001, <0.0001, <0.0001, 0.0038, df = 18–22;p values for hNET – MDMA:p = 0.0312, df = 18; ODMA:p = 0.0013, df = 21; TDMA:p = 0.0005, df = 16). Full statistical reports can be found in the SI.
Figure 2.
Figure 2.
Measurement of transporter-mediated steady-state currents through whole-cell patch clamp (holding voltage (Vh) = −60 mV). (a) Representative single-cell traces showing hSERT-mediated currents elicited by increasing concentration of 5-hydroxytryptamine (5-HT; serotonin) (grey), MDMA (red), ODMA (blue), TDMA (purple), and SeDMA (green). (b) Concentration-response curves at hSERT. Data were normalized to the steady-state current of the saturating concentration of 5-HT (10 μM) and plotted using non-linear regression. The half-maximal effective concentration (EC50) values were extrapolated (5-HT: 0.17 μM < MDMA: 0.27 μM < TDMA: 0.44 μM < SeDMA: 0.77 μM < ODMA: 1.27 μM) as well as the maximum effect (EMAX) values (5-HT: 94%; MDMA: 92.6%; TDMA: 93.2%; SeDMA 97.1%; ODMA: 109.5%). (c) Representative single-cell traces showing hDAT-mediated currents elicited by increasing concentration of DA (grey), MDMA (red), ODMA (blue), TDMA (purple), and SeDMA (green). (d) Concentration-response curves at hDAT. Data were normalized to the steady-state current of the saturating concentration of DA (30 μM) and plotted using non-linear regression. The EC50 values were extrapolated (MDMA: 2.51 μM < ODMA: 3.97 μM < TDMA: 4.29 μM < SeDMA: 5.97 μM < DA: 6.40 μM) as well as the EMAX values (DA: 104.1%; MDMA: 31.9%; ODMA: 48.2%; TDMA: 30.1%; SeDMA: 25.7%). Data are mean ± SD from two to seven individual cells per each concentration (n=2–7).
Figure 3.
Figure 3.
Molecular docking. (a, c) Outward-open structure of hSERT (purple) or hDAT (green cyan) and the binding poses of all ligands (the best pose of 10 independent docking runs) in each transporter. MDMA: salmon, OMDA: blue, TMDA: purple, SeDMA: green and both serotonin (5-HT) and dopamine (DA) in light grey. (b) Left and right panels show the 2D interaction scheme of MDMA and TDMA molecules, respectively, highlighting the main interactions with hSERT (obtained using Maestro version 13.6.122). (d) Left and right panels show the 2D interaction scheme of MDMA and TDMA molecules, respectively, highlighting the main interactions with hDAT (obtained using Maestro version 13.6.122). The asterisks indicate the residues that also interact with 5-HT in hSERT (PDB ID:7MGW) and with DA in dDAT (PDB ID:4XP1). The residues of the protein are shown like guitar picks linked together on a string. The orientation of the guitar pick must be read as: the guitar picks pointing away from the ligand means the backbone of that residue is facing towards the ligand, and when the guitar pick is pointing towards the ligand that means the side chain of that residue is facing the ligand.
Figure 4.
Figure 4.
MDMA activates 5-HT2A, 5-HT2B, and 5-HT2C receptors more potently than its analogs. (a) BRET Gq dissociation assay for human 5-HT2 receptors (5-HT2A-green, 5-HT2B-red, 5-HT2C-blue) using (b) 5-HT as positive control and measuring agonist activity of (c) MDMA compared to MDMA bioisosteric analogs (d) ODMA, (e) TDMA and (f) SeDMA. Data represent mean ± SEM from three independent cell culture preparations (n=3).
Figure 5.
Figure 5.
MDMA and its analogs differ in their hepatic metabolism. (a-c) Metabolic pathways of ODMA, TDMA, and SeDMA in incubations with pooled human liver microsomes. Undefined hydroxylation position is indicated by unspecific bonds. Metabolite-IDs correspond to Table 3. (d) Metabolic pathways of MDMA reported in literature in incubations with pooled human liver microsomes and/or S9 fraction (Richteret al. 2017a; Schwaningeret al. 2011b). Metabolite-IDs correspond to Table 3. (e) Metabolic stability of MDMA (red), ODMA (blue), TDMA (purple), and SeDMA (green) in incubations with pooled human liver microsomes (pHLM). Incubation time is plotted versus the natural logarithm of peak area of the compound. Points indicate mean ± SD from two independent incubations with pHLM (n=2),t1/2 =in vitro half-life.
Figure 6.
Figure 6.
MDMA and its analogs interact with the low-affinity high-capacity human organic cation transporters (hOCT1–3) and human plasma membrane monoamine transporter (hPMAT) at low micromolar concentrations. Uptake-inhibition curves at hOCT1, hOCT2, hOCT3, and hPMAT. Curves were plotted and fitted by non-linear regression, and data were best fitted to a sigmoidal dose-response curve to obtain IC50 values (see Table 6). Data are mean ± SD from three to four independent cell culture preparations (n=3–4), performed in triplicate.
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