5-HT7 receptor modulators: Amino groups attached to biphenyl scaffold determine functional activity

• Published in: European journal of medicinal chemistry 2016-11, Vol.123, p.180-190
• Main Authors: Kim, Youngjae, Park, Hyeri, Lee, Jeongeun, Tae, Jinsung, Kim, Hak Joong, Min, Sun-Joon, Rhim, Hyewhon, Choo, Hyunah
• Format: Article
• Language: English
• Subjects: 5-HT7 receptor; Agonist; Amines - chemistry; Antagonist; Biphenyl Compounds - chemistry; Drug Design; Humans; Ligands; Molecular docking; Molecular Docking Simulation; Protein Binding; Receptors, Serotonin - metabolism; Serotonin; Serotonin Antagonists - chemistry; Serotonin Receptor Agonists - chemistry; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.07.029

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. [Display omitted] •Biphenyl-3-yl-methanamines with various amino groups were designed for 5-HT7R modulators.•Amino groups attached to biphenyl scaffold determine functional activity.•Interaction of the ligand with Arg367 of 5-HT7R is important to differentiate agonists and antagonists.•Two distinct pharmacophore models can tell agonists from antagonists.