Synthesis and antidepressant-like activity of novel aralkyl piperazine derivatives targeting SSRI/5-HT1A/5-HT7

Eur J Med Chem. 2018 Jan 20:144:701-715. doi: 10.1016/j.ejmech.2017.12.063. Epub 2017 Dec 20.

Abstract

A series of novel aralkyl piperazine derivatives were synthesized, and evaluated for their serotonin reuptake inhibitory and 5-HT1A/5-HT7 receptors affinities activity. Antidepressant activities in vivo of the compounds were screened using the forced swimming test (FST) and tail suspension test (TST). The results indicated that compounds 21k (RUI, IC50 = 31 nM; 5-HT1A, 5-HT7, ki = 62, 12 nM) and 21n (RUI, IC50 = 25 nM; 5-HT1A, 5-HT7, ki = 28, 3.3 nM) exhibited high affinities for the 5-HT1A/5-HT7 receptors coupled with potent serotonin reuptake inhibition. Specifically, the most promising compound 21n possessed a good oral pharmacokinetic properties and an acceptable hERG profile, and showed potent antidepressant-like effect in the FST and TST models.

Keywords: 5-HT(1A) receptor; 5-HT(7) receptor; Antidepressant; Serotonin reuptake inhibitory.

MeSH terms

  • Animals
  • Antidepressive Agents / chemical synthesis
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Male
  • Molecular Structure
  • Piperazine
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptors, Serotonin / metabolism*
  • Selective Serotonin Reuptake Inhibitors / chemical synthesis
  • Selective Serotonin Reuptake Inhibitors / chemistry
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antidepressive Agents
  • Piperazines
  • Receptors, Serotonin
  • Serotonin Uptake Inhibitors
  • serotonin 7 receptor
  • Receptor, Serotonin, 5-HT1A
  • Piperazine