TY - JOUR
T1 - Aryl biphenyl-3-ylmethylpiperazines as 5-HT7 receptor antagonists
AU - Kim, Jeeyeon
AU - Kim, Youngjae
AU - Tae, Jinsung
AU - Yeom, Miyoung
AU - Moon, Bongjin
AU - Huang, Xi Ping
AU - Roth, Bryan L.
AU - Lee, Kangho
AU - Rhim, Hyewhon
AU - Choo, I. C.
AU - Chong, Youhoon
AU - Keum, Gyochang
AU - Nam, Ghilsoo
AU - Choo, Hyunah
PY - 2013/11
Y1 - 2013/11
N2 - 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-HT 7R. 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-HT 3R, 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.
AB - 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-HT 7R. 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-HT 3R, 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.
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U2 - 10.1002/cmdc.201300240
DO - 10.1002/cmdc.201300240
M3 - Article
C2 - 24039134
AN - SCOPUS:84890888858
SN - 1860-7179
VL - 8
SP - 1855
EP - 1864
JO - Farmaco
JF - Farmaco
IS - 11
ER -