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

Title
Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression
Authors
김영재태진성이강호임혜원추일한조희영박우규금교창추현아
Keywords
serotonin receptor; 5-HT7R; antagonist; depression; antidepressant
Issue Date
2014-09
Publisher
Bioorganic & medicinal chemistry
Citation
VOL 22, NO 17, 4587-4596
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-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 8.69 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.
URI
http://pubs.kist.re.kr/handle/201004/50196
ISSN
09680896
Appears in Collections:
KIST Publication > Article
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