Discovery of β-Arrestin Biased Ligands of 5-HT7R

J Med Chem. 2018 Aug 23;61(16):7218-7233. doi: 10.1021/acs.jmedchem.8b00642. Epub 2018 Aug 1.


Though many studies have been published about therapeutic potentials of selective 5-HT7R ligands, there have been few biased ligands of 5-HT7R. The development of potent and selective biased ligands of 5-HT7R would be of great help in understanding the relationship between pharmacological effects and G protein/β-arrestin signaling pathways of 5-HT7R. In order to identify 5-HT7R ligands with biased agonism, we designed and synthesized a series of tetrahydroazepine derivatives 1 and 2 with arylpyrazolo moiety or arylisoxazolo moiety. Through several biological evaluations such as binding affinity, selectivity profile, and functions in G protein and β-arrestin signaling pathways, 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4- d]azepine 1g was discovered as the β-arrestin biased ligand of 5-HT7R. In an electroencephalogram (EEG) test, 1g increased total non-rapid eye movement (NREM) sleep time and decreased total rapid eye movement (REM) sleep time.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Azepines / chemistry*
  • Drug Stability
  • Eye Movements / drug effects
  • HEK293 Cells
  • Humans
  • Ligands
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Molecular Docking Simulation
  • Phenols / pharmacology
  • Receptors, Serotonin / metabolism*
  • Serotonin Antagonists / pharmacology
  • Signal Transduction / drug effects
  • Sleep / drug effects*
  • Sleep, REM / drug effects
  • Structure-Activity Relationship
  • Sulfonamides / pharmacology
  • beta-Arrestins / agonists
  • beta-Arrestins / metabolism*


  • Azepines
  • Ligands
  • Phenols
  • Receptors, Serotonin
  • SB 269970
  • Serotonin Antagonists
  • Sulfonamides
  • beta-Arrestins
  • serotonin 7 receptor