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 2024-01-19T14:01:48Z 2024-01-19T14:01:48Z 2021-10-21 2021-09 0022-2623 https://pubs.kist.re.kr/handle/201004/116555 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. English AMER CHEMICAL SOC Discovery of G Protein-Biased Antagonists against 5-HT7R Article 10.1021/acs.jmedchem.1c01093 1 JOURNAL OF MEDICINAL CHEMISTRY, v.64, no.18, pp.13766 - 13779 JOURNAL OF MEDICINAL CHEMISTRY 64 18 13766 13779 N scie scopus 000701513400038 2-s2.0-85115981902 Chemistry, Medicinal Pharmacology & Pharmacy Article COUPLED RECEPTORS SEROTONIN RECEPTORS LIGANDS DESIGN MODEL MOUSE DRUG SCHIZOPHRENIA PHARMACOPHORE OPTIMIZATION autism spectrum disorder GPCR 5-HT7R neurodevelopmental disorders biased antagonist