Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression

Bioorg Med Chem. 2014 Sep 1;22(17):4587-96. doi: 10.1016/j.bmc.2014.07.026. Epub 2014 Jul 25.


5-HT7 receptor (5-HT7R) is a promising target for the treatment of depression and neuropathic pain. 5-HT7R antagonists exhibited antidepressant effects, while the agonists produced strong anti-hyperalgesic effects. In our efforts to discover selective 5-HT7R antagonists or agonists, N-biphenylylmethyl 2-methoxyphenylpiperazinylalkanamides 1 were designed, synthesized, and biologically evaluated against 5-HT7R. Among the synthesized compounds, N-2'-chlorobiphenylylmethyl 2-methoxyphenylpiperazinylpentanamide 1-8 showed the best binding affinity with a Ki value of 8.69nM and it was verified as a novel antagonist according to functional assays. The compound 1-8 was very selective over 5-HT1DR, 5-HT2AR, 5-HT3R, 5-HT5AR and 5-HT6R and moderately selective over 5-HT1AR, 5-HT1BR and 5-HT2CR. The novel 5-HT7R antagonist 1-8 exhibited an antidepressant effect at a dose of 25mg/kg in the forced swimming test in mice and showed a U-shaped dose-response curve which typically appears in 5-HT7R antagonists such as SB-269970 and lurasidone.

Keywords: 5-HT7R; Antagonist; Antidepressant; Depression; Serotonin receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / administration & dosage
  • Amides / chemistry
  • Amides / pharmacology*
  • Animals
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / pharmacology*
  • Depression / drug therapy*
  • HEK293 Cells
  • Humans
  • Injections, Intraperitoneal
  • Male
  • Mice
  • Mice, Inbred ICR
  • Piperazines / administration & dosage
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Receptors, Serotonin / metabolism*
  • Swimming


  • Amides
  • Antidepressive Agents
  • Piperazines
  • Receptors, Serotonin
  • serotonin 7 receptor