Discovery of G Protein-Biased Antagonists against 5?HT7R

Title
Discovery of G Protein-Biased Antagonists against 5?HT7R
Authors
금교창추현아우지완김정진전병선조약돌김도영염미영곽리나이지언이하은김학중
Keywords
autism spectrum disorder; GPCR; 5-HT7R; neurodevelopmental disorders; biased antagonist
Issue Date
2021-09
Publisher
Journal of medicinal chemistry
Citation
VOL 64, NO 18-13779
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.
URI
http://pubs.kist.re.kr/handle/201004/73888
ISSN
0022-2623
Appears in Collections:
KIST Publication > Article
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