Discovery of G Protein-Biased Antagonists against 5-HT7R
| Autor: | Doyoung Kim, Jeongjin Kim, Gyochang Keum, Hak Joong Kim, Rina Kwag, Haeun Lee, Jieon Lee, Yakdol Cho, Byungsun Jeon, Miyoung Yeom, Hyunah Choo, Jiwan Woo |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry. 64:13766-13779 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c01093 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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