Discovery of β-Arrestin Biased Ligands of 5-HT7R

Youngjae Kim, Hyunguk Kim, Jieon Lee, Jae Kyun Lee, Sun Joon Min, Jihye Seong, Hyewhon Rhim, Jinsung Tae, Hyunjoo Jenny Lee, Hyunah Choo

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)7218-7233
Number of pages16
JournalJournal of Medicinal Chemistry
Issue number16
Publication statusPublished - 2018 Aug 23

Bibliographical note

Publisher Copyright:
© 2018 American Chemical Society.

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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