RESUMO
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.
RESUMO
The interaction between two nitrosyl ruthenium complexes [Ru (NH.NHq-COOH)(tpy)NO](PF6 )3 (RuBDQ) and [Ru (NH.NHq-H)(tpy)NO](PF6 )3 (RuBD) and human serum albumin (HSA) was investigated using spectroscopic and computational methods. From fluorescence experiments, a dynamic quenching mechanism and binding constants at a single site demonstrated the higher stability of the RuBDQ-HSA system at 308 K compared with RuBD-HSA. Thermodynamic parameters indicated that binding of RuBDQ and RuBD to HSA was mainly driven by hydrophobic interaction and hydrogen bonding, respectively. Synchronous fluorescence and FT-IR results suggested that interactions between both nitrosyl ruthenium complexes and HSA affected protein conformation. Competition experiments revealed that RuBDQ and RuBD bound to Sudlow sites I and II, respectively. Molecular docking results showed that RuBDQ interacted with Ser-192 and Ala-291 residues via hydrogen bonding and polar contact, respectively, whereas RuBD associated with Asn-391 via a polar interaction. Noncovalent interaction results suggested that van der Waals interactions were the main binding forces for both systems, i.e. RuBDQ associated with Trp-214 via van der Waals interaction and with Ty-150 via dipole-dipole bonding, whereas RuBD associated with Tyr-452 via van der Waals forces. The Asp-391 residue interacted with the nitrosyl ligand via polar contact and the terpyridine ligand via van der Waals interaction.
