title: 5-HT7 receptor modulators: Amino groups attached to biphenyl scaffold determine functional activity.
abstract: 5-HT7 receptor (5-HT7R) agonists and antagonists have been reported to be used for treatment of neuropathic pain and depression, respectively. In this study, as a novel scaffold for 5-HT7R modulators, we designed and prepared a series of biphenyl-3-yl-methanamine derivatives with various amino groups. Evaluation of functional activities as well as binding affinities of the title compounds identified partial agonists (EC50 = 0.55-3.2 μM) and full antagonists (IC50 = 5.57-23.1 μM) depending on the amino substituents. Molecular docking study suggested that the ligand-based switch in functional activity from agonist to antagonist results from the size of the amino groups and thereby different binding modes to 5-HT7R. In particular, interaction of the ligand with Arg367 of 5-HT7R is shown to differentiate agonists and antagonists. In the pharmacophore model study, two distinct pharmacophore models can tell whether a ligand is an agonist or an antagonist. Taken together, this study provides valuable information for designing novel compounds with selective agonistic or antagonistic properties against 5-HT7R.
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Chemistry, College of Science, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Youngjae
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea.
authors.forename: Hyeri
authors.initials: H
authors.lastname: Park
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Chemistry, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Jeongeun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Chemistry, College of Science, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Jinsung
authors.initials: J
authors.lastname: Tae
authors.affiliation: Department of Chemistry, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Hak Joong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Applied Chemistry, Hanyang University, Gyeonggi-du, Ansan 15588, Republic of Korea.
authors.forename: Sun-Joon
authors.initials: SJ
authors.lastname: Min
authors.affiliation: Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Neuroscience, Korea University of Science and Technology, Youseong-gu, Daejeon 34113, Republic of Korea.
authors.forename: Hyewhon
authors.initials: H
authors.lastname: Rhim
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Biological Chemistry, Korea University of Science and Technology, Youseong-gu, Daejeon 34113, Republic of Korea. Electronic address: hchoo@kist.re.kr.
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
mesh_terms: D000588:Amines / Q000737:chemistry; D001713:Biphenyl Compounds / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000737:chemistry; D017366:Serotonin Receptor Agonists / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D001713:Biphenyl Compounds; D008024:Ligands; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C104425:serotonin 7 receptor; C010574:biphenyl
keywords: 5-HT(7) receptor; Agonist; Antagonist; Molecular docking; Serotonin