title: Discovery of aryl-biphenyl-2-ylmethylpiperazines as novel scaffolds for 5-HT(7) ligands and role of the aromatic substituents in binding to the target receptor.
abstract: It has been reported that 5-HT(7) receptors are promising targets of depression and neuropathic pain. 5-HT(7) receptor antagonists have exhibited antidepressant-like profiles, while agonists have represented potential therapeutics for pain. In the course of our ongoing efforts to discover novel 5-HT(7) modulators, we designed an arylpiperazine scaffold with a substituted biphenyl-2-ylmethyl group. A series of biphenyl-2-yl-arylpiperazinylmethanes were then prepared, which showed a broad spectrum of binding affinities to the 5-HT(7) receptor depending upon the substituents attached to the biphenyl and aryl functionalities. Among those synthesized compounds, the compounds 1-24 and 1-26 showed the best binding affinities to the 5-HT(7) receptor with K(i) values of 43.0 and 46.0 nM, respectively. Structure-activity relationship study in conjunction with molecular docking study proposed that the 5-HT(7) receptor might have two distinctive hydrophobic binding sites, one specific for aromatic 2-OCH(3) substituents within the arylpiperazine and the other for biphenyl methoxy group.
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Hwarangro 14-gil-5, Seoul 136-791, Republic of Korea.
authors.forename: Youngjae
authors.initials: Y
authors.lastname: Kim
authors.forename: Jeeyeon
authors.initials: J
authors.lastname: Kim
authors.forename: Jinsung
authors.initials: J
authors.lastname: Tae
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Hyewhon
authors.initials: H
authors.lastname: Rhim
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: D001665:Binding Sites / Q000187:drug effects; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001713:Biphenyl Compounds; D008024:Ligands; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor