Discovery of G Protein-Biased Antagonists against 5-HT7R
- Authors
- Kwag, Rina; Lee, Jieon; Kim, Doyoung; Lee, Haeun; Yeom, Miyoung; Woo, Jiwan; Cho, Yakdol; Kim, Hak Joong; Kim, Jeongjin; Keum, Gyochang; Jeon, Byungsun; Choo, Hyunah
- Issue Date
- 23-9월-2021
- Publisher
- AMER CHEMICAL SOC
- Citation
- JOURNAL OF MEDICINAL CHEMISTRY, v.64, no.18, pp.13766 - 13779
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF MEDICINAL CHEMISTRY
- Volume
- 64
- Number
- 18
- Start Page
- 13766
- End Page
- 13779
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/136319
- DOI
- 10.1021/acs.jmedchem.1c01093
- ISSN
- 0022-2623
- 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 beta-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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