Ação do tipo ansiolítica e antidepressiva do composto 3-((4-metoxifenil)selanil)-2-fenilbenzofurano em camundongos

Abstract

Depression is one of the most common pathologies in modern times and is frequently associated with anxiety disorders. Due to cases of drug resistance, serious adverse effects, or delay in therapeutic response to currently available drugs, several studies have aimed at the pharmacological and toxicological characterization of drug candidates for the treatment of these psychiatric conditions. Compounds of the 3-organoselanyl benzofurans (SeBZF) class have been studied by our research group for their antioxidant and psychotherapeutic properties. For this reason, this study aimed to investigate the anxiolytic and antidepressant-like action of substituted SeBZF compounds (SeBZF2-5) in male Swiss mice, comparing it to its unsubstituted prototype (2-phenyl-3-(phenylselanyl)benzofuran - SeBZF1), i.e., whether the structural modification by the addition of substituents would bring any benefit to the compound. The screening conducted for the detection of an anxiolytic-type potential in the light-dark test (LDT) demonstrated that SeBZF3 (3-((4-methoxyphenyl)selanyl)-2-phenylbenzofuran) alone caused a significant increase in the time spent in the light compartment of the apparatus. In addition, dose- and time-dependent curve data revealed that SeBZF3 exerts antidepressant-like effects in the tail suspension test (TST) (5-50 mg/kg) and forced swim test (FST) (50 mg/kg), causing longer-lasting effects when compared to the previously studied prototype SeBZF1 class. Additional tests were performed with SeBZF3, which features a methoxy substituent, to investigate the possible contribution of the serotoninergic system in the antidepressant-like action of SeBZF3. The anti-immobility effects of the compound on the TST were blocked by pre-administration of serotoninergic receptor antagonists (WAY100635, ketanserin, and ondansetron). In addition, the combined administration of sub-effective doses of SeBZF3 and fluoxetine (a selective serotonin reuptake inhibitor, SSRI) produced a synergistic effect on TST. No changes were detected in the locomotor and exploratory activity of animals exposed to SeBZF3 during the different behavioral sets. Molecular docking studies suggested possible molecular interactions between SeBZF3 and the serotoninergic molecular targets evaluated (5-CT2A and 5-HT2C receptors and serotonin transporter - SERT). Finally, the assay findings for the evaluation of acute oral toxicity at a high dose (300 mg/kg) suggest a relative safety of this compound, as there were no changes in the parameters evaluated. Taken together, the findings of the present study provide evidence for the anxiolytic and antidepressant-type action of SeBZF3 and its low potential to generate serious adverse effects. Furthermore, the data suggest a possible interaction between SeBZF3 and the serotoninergic system. Therefore, SeBZF3 presents itself as a potential candidate to treat psychiatric disorders such as depression and anxiety.