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

14 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

Funding Information:
We are grateful to the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (contract: HHSN-271-2008-00025-C) for providing binding affinity data. This research is supported by the Original Technology Research Program (NRF-2016M3C7A1904344 and 2016M3C7A1904343) funded by the National Research Foundation of Korea (NRF). This work is additionally funded by the Korea Institute of Science and Technology (KIST) Institutional Program (2E27870 and 2E28412).

Publisher Copyright:
© 2018 American Chemical Society.

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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