New arylpiperazine derivatives with antidepressant-like activity containing isonicotinic and picolinic nuclei: evidence for serotonergic system involvement

Abstract

Therapy of depression is difficult and still insufficient despite the presence of many antidepressants on the market. Therefore, there is a constant need to search for new, safer, and more effective drugs that could be used in the treatment of depression. Among many methods, chemical modification is an important strategy for new drug development. This study evaluates antidepressant-like effects and possible mechanism of action of two new arylpiperazine derivatives with isonicotinic and picolinic nuclei, compounds 4pN-(3-(4-(piperonyl)piperazin-1-yl)propyl) isonicotinamide and 3oN-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl) picolinamide. The forced swim test (FST) and tail suspension test (TST), as two predictive tests for antidepressant effect in mice, were used. The possible involvement of serotonergic system in the effects of the new compounds in the FST through pharmacological antagonists/modulators of serotonergic transmission was also investigated. Compounds 4p and 3o were shown to possess antidepressant activity in both tests, FST and TST. The antidepressant-like effects of the new compounds in the FST were prevented by pretreatment of mice with pCPA (serotonin depletor), (−)pindolol (mixed 5-HT1A/1B and β-adrenergic antagonist), and WAY 100635 (selective 5-HT1A antagonist). Additionally, in drug interaction studies, the 5-HT2A/2C antagonist, ketanserin, and the classic antidepressant, imipramine, potentiated antidepressant-like effect of both new compounds. The obtained results demonstrate that the new compounds 4p and 3o produce an antidepressant-like effect in mice which seems to be mediated by interaction with the serotonin 5-HT1A receptors and in the case of 4p, also with the 5-HT2C receptors.