Discovery of G Protein-Biased Ligands against 5-HT7R

J Med Chem. 2021 Jun 10;64(11):7453-7467. doi: 10.1021/acs.jmedchem.1c00110. Epub 2021 May 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Biphenyl Compounds / chemistry*
  • Biphenyl Compounds / metabolism
  • Biphenyl Compounds / pharmacology
  • Drug Evaluation, Preclinical
  • Drug Stability
  • Half-Life
  • Humans
  • Ligands*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Microsomes / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Serotonin / chemistry
  • Receptors, Serotonin / metabolism*
  • Structure-Activity Relationship


  • Biphenyl Compounds
  • Ligands
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Protein Isoforms
  • Receptors, G-Protein-Coupled
  • Receptors, Serotonin
  • Shank3 protein, mouse
  • serotonin 7 receptor
  • diphenyl