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

Eur J Med Chem. 2016 Nov 10:123:180-190. doi: 10.1016/j.ejmech.2016.07.029. Epub 2016 Jul 21.


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.

Keywords: 5-HT(7) receptor; Agonist; Antagonist; Molecular docking; Serotonin.

MeSH terms

  • Amines / chemistry
  • Biphenyl Compounds / chemistry
  • Drug Design*
  • Humans
  • Ligands
  • Molecular Docking Simulation*
  • Protein Binding
  • Receptors, Serotonin / metabolism*
  • Serotonin Antagonists / chemistry
  • Serotonin Receptor Agonists / chemistry
  • Structure-Activity Relationship


  • Amines
  • Biphenyl Compounds
  • Ligands
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • serotonin 7 receptor
  • diphenyl