Discovery of G Protein-Biased Ligands against 5-HT7R

Jieon Lee, Rina Kwag, Soyeon Lee, Doyoung Kim, Jiwan Woo, Yakdol Cho, Hak Joong Kim, Jeongjin Kim, Byungsun Jeon, Hyunah Choo

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


There has been significant attention concerning the biased agonism of G protein-coupled receptors (GPCRs), and it has resulted in various pharmacological benefits. 5-HT7R belongs to a GPCR, and it is a promising pharmaceutical target for the treatment of neurodevelopmental and neuropsychiatric disorders. Based on our previous research, we synthesized a series of 6-chloro-2′-methoxy biphenyl derivatives 1, 2, and 3 with a variety of amine scaffolds. These compounds were evaluated for their binding affinities to 5-HTR subtypes and their functional selectivity toward the Gs protein and the β-arrestin signaling pathways of 5-HT7R. Among them, 2-(6-chloro-2′-methoxy-[1,1′-biphenyl]-3-yl)-N-ethylethan-1-amine, 2b, was found to be a G-protein-biased ligand of 5-HT7R. In an in vivo study with Shank3 transgenic mice, the self-grooming behavior test was performed with 2b, which increased the duration of self-grooming. The experiments further suggested that 5-HT7R is associated with autism spectrum disorders (ASDs) and could be a therapeutic target for the treatment of stereotypy in ASDs.

Original languageEnglish
Pages (from-to)7453-7467
Number of pages15
JournalJournal of Medicinal Chemistry
Issue number11
Publication statusPublished - 2021 Jun 10

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 the Basic Science Research Program (NRF-2021R1A2C2006244) funded by the National Research Foundation of Korea (NRF). In addition, this work is additionally funded by the Korea Institute of Science and Technology (KIST) Institutional Program (2E30961 and 2E30960).

Publisher Copyright:
© 2021 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


Dive into the research topics of 'Discovery of G Protein-Biased Ligands against 5-HT7R'. Together they form a unique fingerprint.

Cite this