Discovery of G Protein-Biased Antagonists against 5-HT7R

  • J Med Chem. 2021 Sep 23;64(18):13766-13779. doi: 10.1021/acs.jmedchem.1c01093.
Rina Kwag  1  2 ,  Jieon Lee  1  3 ,  Doyoung Kim  1  4 ,  Haeun Lee  1  3 ,  Miyoung Yeom  1 ,  Jiwan Woo  5 ,  Yakdol Cho  5 ,  Hak Joong Kim  2 ,  Jeongjin Kim  1 ,  Gyochang Keum  1  3 ,  Byungsun Jeon  1 ,  Hyunah Choo  1  3
Affiliations
  • 1. Brain Science Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea.
  • 2. Department of Chemistry, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea.
  • 3. Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea.
  • 4. Department of Chemistry, Sogang University, Mapo-gu, Seoul 04107, Republic of Korea.
  • 5. Research Animal Resource Center, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea.
PMID: 34519505 DOI: 10.1021/acs.jmedchem.1c01093
Abstract

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.

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