Investigation of serotonergic system-mediated antidepressant-like effects of some piperazine derivative compounds

In this thesis study, 12 original piperazine derivative compounds (2a-2l) were synthesized and the possible antidepressant-like effects of these compounds were investigated. The chemical structures of the synthesized compounds were elucidated using methods such as IR, 1H-NMR, 13C-NMR and mass spectroscopy. Effects of the compounds on motor coordination of mice were evaluated by Rota-rod method; while their antidepressant-like effects were assessed by tail suspension and modified forced swimming tests. None of the compounds in the series caused a significant change in the motor performance of the mice. On the other hand, compounds 2b, 2d, 2g, 2h, 2i and 2j significantly shortened the immobility times of the mice in the tail suspension and modified forced swimming tests with respected to the immobility times of the control group. The same compounds prolonged the swimming behavior of mice in the modified forced swimming test. Obtained data indicated that the compounds 2b, 2d, 2g, 2h, 2i and 2j have antidepressant-like activity. Mechanistic studies were conducted with PCPA, a serotonin synthesis inhibitor agent, and NAN-190, a 5-HT1A serotonergic receptor blocker, to investigate whether the mentioned effect is mediated by the serotonergic system. Both PCPA and NAN-190 pre-treatments reversed the anti-immobility effect of compounds 2b, 2d, 2g, 2h, 2i and 2j. The obtained data indicated that the antidepressant-like effects of these piperazine derivatives are mediated by 5-HT1A serotonergic receptors in the presence of an intact serotonergic system. Studies on the estimation of ADME parameters of the active compounds in this study revealed that the compounds have appropriate pharmacokinetic properties. The findings of this thesis study supported the findings of previous studies pointing to the antidepressant activity potential of piperazine derivative compounds and brought new drug candidate molecules to the literature showing their effects on the serotonergic system.