Premium
Aryl Biphenyl‐3‐ylmethylpiperazines as 5‐HT 7 Receptor Antagonists
Author(s) -
Kim Jeeyeon,
Kim Youngjae,
Tae Jinsung,
Yeom Miyoung,
Moon Bongjin,
Huang XiPing,
Roth Bryan L.,
Lee Kangho,
Rhim Hyewhon,
Choo Il Han,
Chong Youhoon,
Keum Gyochang,
Nam Ghilsoo,
Choo Hyunah
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300240
Subject(s) - piperazine , 5 ht receptor , chemistry , moiety , agonist , serotonin , stereochemistry , aryl , biphenyl , receptor , pharmacology , receptor antagonist , ketanserin , antagonist , medicine , biochemistry , organic chemistry , alkyl
Abstract The 5‐HT 7 receptor (5‐HT 7 R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5‐HT 7 R antagonist SB‐269970 exhibited antidepressant‐like activity, whereas systemic administration of the 5‐HT 7 R agonist AS‐19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5‐HT 7 R antagonists or agonists, aryl biphenyl‐3‐ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5‐HT 7 R. 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‐HT 7 R (p K i =7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5‐HT 7 R over other serotonin receptor subtypes, such as 5‐HT 1 R, 5‐HT 2 R, 5‐HT 3 R, and 5‐HT 6 R. 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.