title: Aryl biphenyl-3-ylmethylpiperazines as 5-HT7 receptor antagonists.
abstract: The 5-HT7 receptor (5-HT7 R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5-HT7 R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT7 R agonist AS-19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5-HT7 R antagonists or agonists, aryl biphenyl-3-ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5-HT7 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-HT7 R (pKi =7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5-HT7 R over other serotonin receptor subtypes, such as 5-HT1 R, 5-HT2 R, 5-HT3 R, and 5-HT6 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.
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791 (Korea); Department of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749 (Korea).
authors.forename: Jeeyeon
authors.initials: J
authors.lastname: Kim
authors.forename: Youngjae
authors.initials: Y
authors.lastname: Kim
authors.forename: Jinsung
authors.initials: J
authors.lastname: Tae
authors.forename: Miyoung
authors.initials: M
authors.lastname: Yeom
authors.forename: Bongjin
authors.initials: B
authors.lastname: Moon
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Kangho
authors.initials: K
authors.lastname: Lee
authors.forename: Hyewhon
authors.initials: H
authors.lastname: Rhim
authors.forename: Il Han
authors.initials: IH
authors.lastname: Choo
authors.forename: Youhoon
authors.initials: Y
authors.lastname: Chong
authors.forename: Gyochang
authors.initials: G
authors.lastname: Keum
authors.forename: Ghilsoo
authors.initials: G
authors.lastname: Nam
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
mesh_terms: D001713:Biphenyl Compounds / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011985:Receptors, Serotonin / Q000737:chemistry*; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C000594011:1-((2'-methoxy-(1,1'-biphenyl)-3-yl)methyl)-4-(2-methoxyphenyl)piperazine; D001713:Biphenyl Compounds; D008024:Ligands; D010636:Phenols; D010879:Piperazines; D011985:Receptors, Serotonin; C404922:SB 269970; D012702:Serotonin Antagonists; D013449:Sulfonamides; C104425:serotonin 7 receptor
keywords: antagonists; aryl piperazines; biaryls; receptors; structure-activity relationships