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

Youngjae Kim, Jinsung Tae, Kangho Lee, Hyewhon Rhim, Il Han Choo, Heeyeong Cho, Woo Kyu Park, Gyochang Keum, Hyunah Choo

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20 Citations (Scopus)


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-HT 7R 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 8.69 nM 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 25 mg/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.

Original languageEnglish
Pages (from-to)4587-4596
Number of pages10
JournalBioorganic and Medicinal Chemistry
Issue number17
Publication statusPublished - 2014 Sept 1

Bibliographical note

Funding Information:
Binding affinity data were generously provided by the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (Contract: HHSN-271-2008-00025-C). This research was supported by the Basic Science Research Program (NRF-2013-R1A1A2A10009907) funded by the National Research Foundation of Korea (NRF). Additional funding was provided by the Korea Institute of Science and Technology (KIST) Institutional Program (2E24510).

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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