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

5-HT7R binding assay: Ki 8.69nM. 5-HT7R functional assay: 76.2% inhibition at 10μM. Forced swimming test: 84.9% reduced immobilization at an ip dose of 25mg/kg. 5-HT7 receptor (5-HT7R) is a promising target for the treatment of depression and neuropathic pain. 5-HT7R antagonists exhibited antidepres...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2014-09, Vol.22 (17), p.4587-4596
Main Authors: Kim, Youngjae, Tae, Jinsung, Lee, Kangho, Rhim, Hyewhon, Choo, Il Han, Cho, Heeyeong, Park, Woo-Kyu, Keum, Gyochang, Choo, Hyunah
Format: Article
Language:English
Subjects:
5-HT7R
Amides - administration & dosage
Amides - chemistry
Amides - pharmacology
Animals
Antagonist
Antidepressant
Antidepressive Agents - administration & dosage
Antidepressive Agents - chemistry
Antidepressive Agents - pharmacology
Depression
Depression - drug therapy
HEK293 Cells
Humans
Injections, Intraperitoneal
Male
Mice
Mice, Inbred ICR
Piperazines - administration & dosage
Piperazines - chemistry
Piperazines - pharmacology
Receptors, Serotonin - metabolism
Serotonin receptor
Swimming
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Summary:5-HT7R binding assay: Ki 8.69nM. 5-HT7R functional assay: 76.2% inhibition at 10μM. Forced swimming test: 84.9% reduced immobilization at an ip dose of 25mg/kg. 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2014.07.026