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

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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
Volume22
Issue number17
DOIs
Publication statusPublished - 2014 Sep 1

Fingerprint

Antidepressive Agents
Therapeutics
Serotonin Receptor Agonists
Serotonin Antagonists
Neuralgia
Assays
Serotonin
serotonin 7 receptor
diphenyl
8-1 compound
Lurasidone Hydrochloride
SB 269970
Swimming

All Science Journal Classification (ASJC) codes

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

Cite this

Kim, Youngjae ; Tae, Jinsung ; Lee, Kangho ; Rhim, Hyewhon ; Choo, Il Han ; Cho, Heeyeong ; Park, Woo Kyu ; Keum, Gyochang ; Choo, Hyunah. / Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 22, No. 17. pp. 4587-4596.
@article{be73d16135084b7c87dffa8af26baec3,
title = "Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression",
abstract = "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.",
author = "Youngjae Kim and Jinsung Tae and Kangho Lee and Hyewhon Rhim and Choo, {Il Han} and Heeyeong Cho and Park, {Woo Kyu} and Gyochang Keum and Hyunah Choo",
year = "2014",
month = "9",
day = "1",
doi = "10.1016/j.bmc.2014.07.026",
language = "English",
volume = "22",
pages = "4587--4596",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "17",

}

Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression. / Kim, Youngjae; Tae, Jinsung; Lee, Kangho; Rhim, Hyewhon; Choo, Il Han; Cho, Heeyeong; Park, Woo Kyu; Keum, Gyochang; Choo, Hyunah.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 17, 01.09.2014, p. 4587-4596.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression

AU - Kim, Youngjae

AU - Tae, Jinsung

AU - Lee, Kangho

AU - Rhim, Hyewhon

AU - Choo, Il Han

AU - Cho, Heeyeong

AU - Park, Woo Kyu

AU - Keum, Gyochang

AU - Choo, Hyunah

PY - 2014/9/1

Y1 - 2014/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84906939234&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906939234&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2014.07.026

DO - 10.1016/j.bmc.2014.07.026

M3 - Article

VL - 22

SP - 4587

EP - 4596

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 17

ER -