Antidepressant-like effect of tofisopam in mice: A behavioural, molecular docking and MD simulation study

Abstract

Background: Depression is a disease that affects millions of people worldwide, and the discovery and development of effective and safe antidepressant drugs is one of the important topics of psychopharmacology. Objectives: In this study, it was aimed to investigate the antidepressant-like activity potential of tofisopam, an anxiolytic drug with 2,3-benzodiazepine structure, and to elucidate the pharmacological mechanisms mediating this effect. Methods: The antidepressant-like activity of tofisopam was investigated using tail suspension and modified forced swimming tests. Possible interactions of tofisopam with µ- and δ-opioid receptor subtypes were clarified by pharmacological antagonism, molecular docking and molecular dynamics simulation studies. Results: Tofisopam (50 and 100 mg/kg) significantly shortened the immobility time of mice in both the tail suspension and the modified forced swimming tests. The drug, at the same doses, prolonged the duration of swimming and climbing behaviours measured in modified forced swimming tests. A dosage of 25 mg/kg was ineffective. Mechanistic studies showed that the pretreatment with p-chlorophenylalanine methyl ester (serotonin synthesis inhibitor; 4 consecutive days, 100 mg/kg), α-methyl-para-tyrosine methyl ester (catecholamine synthesis inhibitor; 100 mg/kg), naloxonazine (selective µ-opioid receptor blocker, 7 mg/kg) and naltrindole (a selective δ-opioid receptor blocker, 0.99 mg/kg) abolished the anti-immobility effect induced by the 50 mg/kg dose of tofisopam in the tail suspension tests. Our in silico studies supported the behavioural findings that the antidepressant-like effect of tofisopam is mediated by μ- and δ-opioid receptors. Conclusion: This study is the first to show that tofisopam has antidepressant-like activity mediated by the serotonergic, catecholaminergic and opioidergic systems.

Design, Synthesis, and In Vitro and In Silico Approaches of Novel Indanone Derivatives as Multifunctional Anti-Alzheimer Agents

“…All MDS were carried out for 100 ns to analyze the stability of the identified hits from the in vitro with docking results. System setup preparation, MDS, and interaction analysis calculations were carried out according to the same procedure from previous studies. , …”

“…System setup preparation, MDS, and interaction analysis calculations were carried out according to the same procedure from previous studies. 24 , 40 …”

Design and synthesis of phenoxy methyl‐oxadiazole compounds against Alzheimer's disease

“…Molecular dynamic simulations included calculations of radius of gyration (Rg), root‐mean‐square fluctuation (RMSF), and root‐mean‐square deviation (RMSD) via the Desmond application. [ 29,49,50 ]…”

Focusing on the moderately active compound (MAC) in the design and development of strategies to optimize the apoptotic effect by molecular mechanics techniques

“…In this study, MDS for 100 ns was carried out to ensure the stability of the identified hits from the docking results, and then the interaction types and strengths were analyzed. The method was applied similarly to our previous studies [14,[22][23][24]. Using the standard force field (OPLS3e) of Schrodinger's Suite with a transferable intermolecular potential with 3 points (TIP3P) water model followed by energy minimization of the complex in the Desmond application [25].…”