Discovery of G Protein-Biased Antagonists against 5？HT7R
- Discovery of G Protein-Biased Antagonists against 5？HT7R
- 금교창; 추현아; 우지완; 김정진; 전병선; 조약돌; 김도영; 염미영; 곽리나; 이지언; 이하은; 김학중
- autism spectrum disorder; GPCR; 5-HT7R; neurodevelopmental disorders; biased antagonist
- Issue Date
- Journal of medicinal chemistry
- VOL 64, NO 18-13779
- 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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