Multi-Tissue Transcriptomic-Informed In Silico Investigation of Drugs for the Treatment of Dengue Fever Disease

Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico–informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, “Adrenergic receptor antagonist”, “ATPase inhibitor”, “NF-kB pathway inhibitor” and “Serotonin receptor antagonist”, were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.

Synthesis and Development of Indole Based 5-HT3 Receptor Antagonists as Anti-Emetic Drugs in Oncology: An Update

: An important group of anti-emetic drugs used in the treatment of nausea and vomiting after chemotherapy contains an indole moiety in their structures, working as 5-hydroxytryptamine type 3 serotonin receptor antagonist (5-HT3). This revision is focused on compounds bearing an indole core that present a 5-HT3 receptor antagonist activity that has been successfully used as anti-emetic drugs, reducing chemotherapy adverse secondary effects during cancer treatment. Their synthesis, biological activities, and some outstanding characteristics are discussed, affording a general outlook towards the development of more efficient anti-emetic drugs.

Tumor-suppressive function of methiothepin in human placental choriocarcinoma cells

Placental choriocarcinoma is a malignant trophoblastic tumor associated with placentation. During placentation, complicated molecular networks are mediated by endocrine and paracrine signals. Serotonin neurotransmitters have been identified in the transmembrane region of human placental choriocarcinoma (HPC) cells as tumor promoters; therefore, their antagonists have anti-cancer properties. Although methiothepin, a serotonin receptor antagonist and FDA-approved psychotropic agent, has shown multi-pharmacological functions in various disease models, its anti-tumorigenic activity and mechanisms underlying its action against HPC are unknown. Therefore, we identified the anti-cancer effects of methiothepin in JEG3 and JAR HPC cells. Methiothepin attenuated mitochondrial function and induced endoplasmic reticular stress, reducing oxidative phosphorylation and causing metabolic shifting in HPC cells. Furthermore, methiothepin showed synergistic pharmacological effects with paclitaxel in HPC cells. Our results highlight the robust tumor-suppressive function of methiothepin in HPC. Our findings provide new insights into the repositioning of methiothepin from a psychotropic agent to novel anti-cancer agents, especially against HPC.

The reducing effect of agomelatine on pentylenetetrazol-induced convulsions

Introduction Agomelatine is a potent MT1 and MT2 melatonin receptor agonist and a 5-HT2C serotonin receptor antagonist. The purpose of this study was to show the convulsion-reducing effect of agomelatine, in both clinical and electrophysiological terms, in a pentylenetetrazole (PTZ)-induced experimental epilepsy model in rats. Methods The anticonvulsant activity of agomelatine (25 and 50 mg/kg) was evaluated in rat models of PTZ (35 and 70 mg/kg) and compared with the control groups. Results Agomelatine administration at doses of 25 and 50 mg/kg resulted in a statistically significant decrease in convulsion scores and time to onset of myoclonic jerks compared to the control groups. In addition, comparison of the two doses employed showed that high-dose agomelatine (50 mg/kg) was significantly more effective than the lower dose. In addition to previous studies, we investigated the anticonvulsant effect of agomelatine using electroencephalogram (EEG). Administration of agomelatine at doses of 25 and 50 mg/kg in PTZ-induced seizures caused a significant decrease in the percentage of peak at EEG. Discussion Our results suggest that agomelatine has anticonvulsant activity shown in PTZ-induced seizure model. The results also give some evidences that agomelatine can use on epileptic seizures, but more studies are needed.

Azologization of serotonin 5-HT3 receptor antagonists

The serotonin 5-hydroxytryptamine 3 receptor (5-HT3R) plays a unique role within the seven classes of the serotonin receptor family, as it represents the only ionotropic receptor, while the other six members are G protein-coupled receptors (GPCRs). The 5-HT3 receptor is related to chemo-/radiotherapy provoked emesis and dysfunction leads to neurodevelopmental disorders and psychopathologies. Since the development of the first serotonin receptor antagonist in the early 1990s, the range of highly selective and potent drugs expanded based on various chemical structures. Nevertheless, on-off-targeting of a pharmacophore’s activity with high spatiotemporal resolution as provided by photopharmacology remains an unsolved challenge bearing additionally the opportunity for detailed receptor examination. In the presented work, we summarize the synthesis, photochromic properties and in vitro characterization of azobenzene-based photochromic derivatives of published 5-HT3R antagonists. Despite reported proof of principle of direct azologization, only one of the investigated derivatives showed antagonistic activity lacking isomer specificity.

Can typical and atypical antipsychotics show differential effectiveness in treating paranoia and hallucinations in schizophrenia?

A dopamine excess is thought to be involved in positive psychotic symptoms in schizophrenia. All current antipsychotics show a degree of dopamine receptor antagonism. Little is known about the differential effectiveness of different antipsychotics in treating specific sets of symptoms. We report the case of a 35-year-old man with schizophrenia who presented with prominent hallucinatory symptoms (Positive and Negative Syndrome Scale [PANSS] P1=5, P3=5, P6=5) resistant to high doses of a dopamine, serotonin receptor antagonist, olanzapine. Switching from olanzapine to zuclopenthixol, a dopamine D2 receptor antagonist, led to a complete shift of his symptomatology: his hallucinations abated, however, he presented as very highly paranoid (PANSS P1=6, P3=2, P6=7). On a combination of both antipsychotics, his symptoms subsided (PANSS P1=3, P3=2, P6=2). We discuss the potential for differential effectiveness of different antipsychotic medications in treating hallucinations and paranoia. We argue that future studies could address this question by stratifying patients based on symptoms.