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

doi:10.1021/acs.jmedchem.8b00642

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

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

14 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 language	English
Pages (from-to)	7218-7233
Number of pages	16
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	16
DOIs	https://doi.org/10.1021/acs.jmedchem.8b00642
Publication status	Published - 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

Access to Document

10.1021/acs.jmedchem.8b00642

Cite this

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title = "Discovery of β-Arrestin Biased Ligands of 5-HT7R",

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.",

author = "Youngjae Kim and Hyunguk Kim and Jieon Lee and Lee, {Jae Kyun} and Min, {Sun Joon} and Jihye Seong and Hyewhon Rhim and Jinsung Tae and Lee, {Hyunjoo Jenny} and Hyunah Choo",

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: {\textcopyright} 2018 American Chemical Society.",

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AU - Kim, Youngjae

AU - Kim, Hyunguk

AU - Lee, Jieon

AU - Lee, Jae Kyun

AU - Min, Sun Joon

AU - Seong, Jihye

AU - Rhim, Hyewhon

AU - Tae, Jinsung

AU - Lee, Hyunjoo Jenny

AU - Choo, Hyunah

N1 - 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.

PY - 2018/8/23

Y1 - 2018/8/23

N2 - 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.

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