Discovery of G Protein-Biased Antagonists against 5-HT7R

Rina Kwag, Jieon Lee, Doyoung Kim, Haeun Lee, Miyoung Yeom, Jiwan Woo, Yakdol Cho, Hak Joong Kim, Jeongjin Kim, Gyochang Keum, Byungsun Jeon, Hyunah Choo

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


5-HT7R belongs to a family of G protein-coupled receptors and is associated with a variety of physiological processes in the central nervous system via the activation of the neurotransmitter serotonin (5-HT). To develop selective and biased 5-HT7R ligands, we designed and synthesized a series of pyrazolyl-diazepanes 2 and pyrazolyl-piperazines 3 , which were evaluated for binding affinities to 5-HTR subtypes and functional selectivity for G protein and β-arrestin signaling pathways of 5-HT7R. Among them, 1-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)-1,4-diazepane 2c showed the best binding affinity for 5-HT7R and selectivity over other 5-HTR subtypes. It was also revealed as a G protein-biased antagonist. The self-grooming behavior test was performed with 2c in vivo with Shank3-/-transgenic (TG) mice, wherein 2c significantly reduced self-grooming duration time to the level of wild-type mice. The results suggest that 5-HT7R could be a potential therapeutic target for treating autism spectrum disorder stereotypy.

Original languageEnglish
Pages (from-to)13766-13779
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number18
Publication statusPublished - 2021 Sept 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 Basic Science Research Program (NRF-2021R1A2C2006244) and the Original Technology Research Program (NRF-2016M3C7A1904344), funded by the National Research Foundation of Korea (NRF). The Korea Institute of Science and Technology (KIST) Institutional Program (2E30961 and 2E30963) provided additional funding.

Publisher Copyright:
© 2021 American Chemical Society

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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