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

Fingerprint

Arrestin
Ligands
GTP-Binding Proteins
Sleep
Azepines
REM Sleep
Eye Movements
Electroencephalography
Pharmacology

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Kim, Y., Kim, H., Lee, J., Lee, J. K., Min, S. J., Seong, 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
Kim, Youngjae ; Kim, Hyunguk ; Lee, Jieon ; Lee, Jae Kyun ; Min, Sun Joon ; Seong, Jihye ; Rhim, Hyewhon ; Tae, Jinsung ; Lee, Hyunjoo Jenny ; Choo, Hyunah. / Discovery of β-Arrestin Biased Ligands of 5-HT7R. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 16. pp. 7218-7233.
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Kim, Y, Kim, H, Lee, J, Lee, JK, Min, SJ, Seong, J, Rhim, H, Tae, J, Lee, HJ & Choo, H 2018, 'Discovery of β-Arrestin Biased Ligands of 5-HT7R', Journal of Medicinal Chemistry, vol. 61, no. 16, pp. 7218-7233. https://doi.org/10.1021/acs.jmedchem.8b00642

Discovery of β-Arrestin Biased Ligands of 5-HT7R. / Kim, Youngjae; Kim, Hyunguk; Lee, Jieon; Lee, Jae Kyun; Min, Sun Joon; Seong, Jihye; Rhim, Hyewhon; Tae, Jinsung; Lee, Hyunjoo Jenny; Choo, Hyunah.

In: Journal of Medicinal Chemistry, Vol. 61, No. 16, 23.08.2018, p. 7218-7233.

Research output: Contribution to journalArticle

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AU - Seong, Jihye

AU - Rhim, Hyewhon

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AU - Lee, Hyunjoo Jenny

AU - Choo, Hyunah

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Kim Y, Kim H, Lee J, Lee JK, Min SJ, Seong J et al. Discovery of β-Arrestin Biased Ligands of 5-HT7R. Journal of Medicinal Chemistry. 2018 Aug 23;61(16):7218-7233. https://doi.org/10.1021/acs.jmedchem.8b00642