Antidepressant-like Effect of 1-(2-(4-(4-Ethylphenyl)-1H-1,2,3-triazol-1-yl)phenyl)ethan-1-one in Mice: Evidence of the Contribution of the Serotonergic System

Major depressive disorder (MDD) is a psychiatric disorderthataffects a large portion of the population, with dysregulation of theserotonergic system, which is deeply involved in both the pathophysiologyof MDD and mechanism of action of many antidepressants. Current pharmacologicaltherapies do not meet the neurobiological needs of all depressed individuals,making the development of new antidepressants necessary. In recentdecades, compounds containing triazoles have become promising dueto their range of biological activities, including antidepressantactivity. In this study, we evaluated the antidepressant-like effectof a hybrid containing triazole and acetophenone, 1-(2-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)phenyl)ethan-1-one (ETAP) (0.5-5mg/kg), in the forced swimming test (FST) and tail suspension test(TST) in mice, as well as the involvement of the serotonergic systemin this effect. Our findings demonstrated that ETAP exhibited an antidepressant-likeeffect from the dose of 1 mg/kg and that this effect is modulatedby 5-HT2A/2C and 5-HT4 receptors. We also demonstratedthat this effect may be related to inhibition of monoamine oxidaseA activity in the hippocampus. Additionally, we evaluated the in silico pharmacokinetic profile of ETAP, which predictedits penetration into the central nervous system. ETAP exhibited alow potential for toxicity at a high dose, making this molecule interestingfor the development of a new therapeutic strategy for MDD.

Automated summary

This study evaluated the antidepressant-like effect of a hybrid compound containing triazole and acetophenone, demonstrating that it modulates the serotonergic system through 5-HT2A/2C and 5-HT4 receptors and inhibits monoamine oxidase A activity in the hippocampus. The compound showed penetration into the central nervous system and low toxicity at a high dose, making it an interesting candidate for the development of a new therapeutic strategy for major depressive disorder (MDD).