Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice

Abstract

A series of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles with different substituents were screened for their binding affinity with serotonin transporter (SERT) and dopamine transporter (DAT) by docking molecular. 5-(4methoxyphenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (SeTACN) exhibited the best conformation with SERT even higher than fluoxetine and serotonin, suggesting a competitive inhibition. SeTACN demonstrated additional affinity to other serotonergic receptors involved in antidepressant effects: 5HT1a, 5HT2a and 5HT3. In another set of experiments, SeTACN led to significant reductions in the immobility time of mice submitted to forced swimming test (FST) in the dose range of 0.1- 20mg/kg, suggesting an antidepressant-like effect. The possible mechanism of action was investigated using serotonergic and dopaminergic antagonists. The antidepressant-like effect of SeTACN (0.1mg/kg i.g.) was prevented by the pretreatment with WAY100635 (a selective 5HT1a antagonist), ketanserin (a 5HT2a/c antagonist) and ondansetron (a selective 5ht3 antagonist), PCPA (an inhibitor of serotonin synthesis) but not with SCH23390 (dopaminergic D1 antagonist) and sulpiride (D2 antagonist). Sub-effective dose of fluoxetine was able to potentiate the effects of a sub-effective dose of SeTACN in FST. None of the treatments affected locomotor activity in open field test (OFT). These results together, suggest that the SeTACN antidepressant-like effect is mediate, at least in parts, by serotonergic system.

Antidepressant activity of Spathodea campanulata in mice and predictive affinity of spatheosides towards type A monoamine oxidase

“…In particular, any dysfunctioning of the serotonergic neurotransmission system, leading to lower levels of serotonin (5-HT) and 5-HIAA (the major metabolite of 5-HT) in the brain, contributes greatly to the pathogenesis of depression (32)(33)(34). Thus, the serotonergic system is considered to be the most promising target for the management of psychological disorders (35). MESC exhibited impressive antidepressant activity in FST and in TST possibly via modifying multifaceted serotonergic neurotransmission and reducing the levels of 5-HIAA (36).…”

Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

“…A similar strategy was used to discover the potential inhibitors for sodium-glucose cotransporter-2 (SGLT2, SLC5A2) . Additionally, docking was used to reveal the potential binding sites , or investigate the interacting mechanism of ligands on targets, such as apical sodium-dependent bile acid transporter (ASBT, SLC10A2), norepinephrine transporter (NET), organic cation transporter 1 (OCT1, SLC22A1), and so on. , More recently, a systematic structure-based method combing Gaussian-accelerated molecular dynamics (GaMD) simulation and docking was performed to explore allosteric sites on DAT in inward-open conformation and to screen hit compounds with allosteric affinity . Meanwhile, docking of 200 million small molecules against the inward-open state of the SERT identified lead compound stabilized an outward-closed state of the SERT with little activity against common off-targets which confirmed by cryo-EM structure …”