Aryl Biphenyl-3-ylmethylpiperazines as 5-HT7 Receptor Antagonists

Title
Aryl Biphenyl-3-ylmethylpiperazines as 5-HT7 Receptor Antagonists
Authors
김지연김영재태진성염미영문봉진Xi-Ping HuangBryan L. Roth이강호임혜원추일한정유훈금교창남길수추현아
Keywords
serotonin; 5-HT7; GPCR; depression; selectivity
Issue Date
2013-11
Publisher
CHEMMEDCHEM
Citation
VOL 8, NO 11, 1855-1864
Abstract
The 5-HT7 receptor (5-HT7R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5- HT7R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT7R agonist AS- 19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5-HT7R antagonists or agonists, aryl biphenyl-3-ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5-HT7R. Among the synthesized compounds, 1-([2’-methoxy- (1,1’-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)piperazine (28) was the best binder to the 5-HT7R (pKi=7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5-HT7R over other serotonin receptor subtypes, such as 5-HT1R, 5- HT2R, 5-HT3R, and 5-HT6R. In a molecular modeling study, the 2-methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function.
URI
http://pubs.kist.re.kr/handle/201004/46204
ISSN
18607179
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KIST Publication > Article
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