Design, synthesis, and biological evaluation of piperazine derivatives involved in the 5-HT_1AR/BDNF/PKA pathway

Abstract

In this study, four series of piperazine derivatives were designed, synthesised and subjected to biological test, and compound 6a with potential antidepressant activity was obtained. An affinity assay of compound 6a with 5-hydroxytryptamine (serotonin, 5-HT)_1A receptor (5-HT_1AR) was undertaken, and the effects on the 5-HT level in the brains of mice were also tested. The results showed that compound 6a had the best affinity with 5-HT_1AR (K_i = 1.28 nM) and significantly increased the 5-HT level. The expression levels of 5-HT_1AR, BDNF, and PKA in the hippocampus were analysed by western blot and immunohistochemistry analyses. The results showed that the expression of 5-HT_1AR, BDNF, and PKA in the model group was reduced compared to that of the control group, and compound 6a could reverse this phenomenon. Molecular docking was performed to investigate the interactions of the studied compound 6a with 5-HT_1AR on the molecular level.

Graphical Abstract

Keywords:

• Piperazine
• antidepressant
• western blot
• 5-HT_1AR
• molecular docking studies

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Natural Science Foundation of Shandong (No. ZR2022MB064); “Guangyue Young Scholar Innovation Team” of Liaocheng University (No. LCUGYTD2022-04).