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

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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