Bioisosteric analogs of MDMA with improved pharmacological profile.

3,4-Methylenedioxymethamphetamine (MDMA, ' ecstasy' ) is re-emerging in clinical settings as a candidate for the treatment of specific psychiatric 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 incubation with 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 and dopamine transporters (hSERT and hDAT, respectively) but decreased activity at 5-HT 2A/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. Additional screening for their interaction with human organic cation transporters (hOCTs) and plasma membrane transporter (hPMAT) revealed a weaker interaction of the MDMA analogs with hOCT1, hOCT2, and hPMAT. Our findings suggest that these new MDMA analogs might constitute appealing therapeutic alternatives to MDMA, sparing the primary pharmacological activity at hSERT and hDAT, but displaying a reduced activity at 5-HT 2A/2B/2C receptors and reduced hepatic metabolism. Whether these MDMA bioisosteres may pose lower risk alternatives to the clinically re-emerging MDMA warrants further studies.

Free energy profile of the substrate-induced occlusion of the human serotonin transporter.

The serotonin transporter (SERT) is a member of the Solute Carrier 6 (SLC6) family and is responsible for maintaining the appropriate level of serotonin in the brain. Dysfunction of SERT has been linked to several neuropsychiatric disorders, including depression, anxiety and obsessive-compulsive disorder. Therefore, an in-depth understanding of the mechanism on an atomistic level, coupled with a quantification of transporter dynamics and the associated free energies is required. Here, we constructed Markov state models (MSMs) from extensive unbiased molecular dynamics simulations to quantify the free energy profile of serotonin (5HT) triggered SERT occlusion and explored the driving forces of the mechanism of occlusion. Our results reveal that SERT occludes via multiple intermediate conformations and show that the motion of occlusion is energetically downhill for the 5HT-bound transporter. Force distribution analyses show that the interactions of 5HT with the bundle domain are crucial. During occlusion, attractive forces steadily increase and pull on the bundle domain, which leads to SERT occlusion. Some interactions become repulsive upon full occlusion, suggesting that SERT creates pressure on 5HT to promote its movement towards the cytosol.

Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors.

The presynaptic serotonin transporter (SERT) clears extracellular serotonin following vesicular release to ensure temporal and spatial regulation of serotonergic signalling and neurotransmitter homeostasis. Prescription drugs used to treat neurobehavioral disorders, including depression, anxiety, and obsessive-compulsive disorder, trap SERT by blocking the transport cycle. In contrast, illicit drugs of abuse like amphetamines reverse SERT directionality, causing serotonin efflux. Both processes result in increased extracellular serotonin levels. By combining molecular dynamics simulations with biochemical experiments and using a homologous series of serotonin analogues, we uncovered the coupling mechanism between the substrate and the transporter, which triggers the uptake of serotonin. Free energy analysis showed that only scaffold-bound substrates could initiate SERT occlusion through attractive long-range electrostatic interactions acting on the bundle domain. The associated spatial requirements define substrate and inhibitor properties, enabling additional possibilities for rational drug design approaches.

Polymyxin for treatment of ventilator-associated pneumonia in a setting of high carbapenem resistance.

OBJECTIVES: To analyse the use of polymyxins for the treatment of ventilator-associated pneumonia (VAP) at a teaching hospital where carbapenem-resistant gram-negative bacteria are endemic. PATIENTS AND METHODS: This was a historical cohort study of patients receiving polymyxins to treat VAP in ICUs at a public university hospital in southern Brazil between January 1, 2017 and January 31, 2018. RESULTS: During the study period, 179 cases of VAP were treated with polymyxins. Of the 179 patients, 158 (88.3%) were classified as having chronic critical illness. Death occurred in 145 cases (81.0%). Multivariate analysis showed that the factors independently associated with mortality were the presence of comorbidities (P<0.001) and the SOFA score of the day of polymyxin prescription (P<0.001). Being a burn patient was a protective factor for mortality (P<0.001). Analysis of the 14-day survival probability showed that mortality was higher among the patients who had sepsis or septic shock at the time of polymyxin prescription (P = 0.028 and P<0.001, respectively). Acinetobacter baumannii was identified as the etiological agent of VAP in 121 cases (67.6%). In our cohort, polymyxin consumption and the incidence density of VAP were quite high. CONCLUSIONS: In our study, comprised primarily of chronically critically ill patients, there was a high prevalence of VAP caused by multidrug-resistant bacteria, consistent with healthcare-associated infections in low- and middle-income countries. Presence of comorbidities and the SOFA score at the time of polymyxin prescription were predictors of mortality in this cohort. Despite aggressive antimicrobial treatment, mortality was high, stressing the need for antibiotic stewardship.

Effectiveness of exergaming in improving functional balance, fatigue and quality of life in Parkinson's disease: A pilot randomized controlled trial.

Although motor symptoms in Parkinson's disease (PD) are well established, few studies have described the effects of exergaming on the clinical and functional outcomes of PD. OBJECTIVES: To analyze the effectiveness of exergaming in improving functional balance, fatigue, functional exercise capacity and quality of life in PD. METHODS: The study population consisted of 20 patients (12 males and 8 females) aged 61 ± 9.11 years allocated into two groups: an exergaming group (EGG) (n = 10) and a conventional exercise, or control, group (CG) (n = 10). The following variables were evaluated: functional balance (Berg Scale), fatigue (Fatigue Severity Scale), functional exercise capacity (Six-Minute Walk Test) and quality of life (PDQ-39 Quality of Life Questionnaire). RESULTS: RM-ANOVA showed that balance and fatigue differed significantly between time points: balance [F(1.29, 23.33) = 4.16, p = 0.043] and fatigue [F(2,36) = 5.96, p = 0.006]. In both cases post hoc Bonferroni testing revealed an improvement after 12 weeks of exergaming (p = 0.033 and p = 0.000, respectively). However, this benefit was not sustained after 60 days of follow-up for either outcome. There were no differences in functional exercise capacity or quality of life between the two groups after 12 weeks of treatment. CONCLUSION: Exergaming was effective in enhancing balance and reducing fatigue in PD patients after 12 weeks of treatment, but this benefit was not sustained in the long-term.