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 journalArticle

3 Citations (Scopus)

Abstract

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
Volume61
Issue number16
DOIs
Publication statusPublished - 2018 Aug 23

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Discovery of β-Arrestin Biased Ligands of 5-HT<sub>7</sub>R'. Together they form a unique fingerprint.

  • Cite this

    Kim, Y., Kim, H., Lee, J., Lee, J. K., Min, S. J., Seong, J., Rhim, H., Tae, J., Lee, H. J., & Choo, H. (2018). Discovery of β-Arrestin Biased Ligands of 5-HT7R. Journal of Medicinal Chemistry, 61(16), 7218-7233. https://doi.org/10.1021/acs.jmedchem.8b00642