Kim, Youngjae Kim, Hyunguk Lee, Jieon Lee, Jae Kyun Min, Sun-Joon Seong, Jihye Rhim, Hyewhon Tae, Jinsung Lee, Hyunjoo Jenny Choo, Hyunah 2024-01-19T22:03:55Z 2024-01-19T22:03:55Z 2021-09-03 2018-08 0022-2623 https://pubs.kist.re.kr/handle/201004/121097 Though many studies have been published about therapeutic potentials of selective 5-HT7R ligands, there have been few biased ligands of 5-HT7R. The development of potent and selective biased ligands of 5-HT7R would be of great help in understanding the relationship between pharmacological effects and G protein/beta-arrestin signaling pathways of 5-HT7R. In order to identify 5-HT7R ligands with biased agonism, we designed and synthesized a series of tetrahydroazepine derivatives 1 and 2 with arylpyrazolo moiety or arylisoxazolo moiety. Through several biological evaluations such as binding affinity, selectivity profile, and functions in G protein and beta-arrestin signaling pathways, 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine 1g was discovered as the beta-arrestin biased ligand of 5-HT7R. In an electroencephalogram (EEG) test, 1g increased total non-rapid eye movement (NREM) sleep time and decreased total rapid eye movement (REM) sleep time. English American Chemical Society Discovery of beta-Arrestin Biased Ligands of 5-HT7R Article 10.1021/acs.jmedchem.8b00642 1 Journal of Medicinal Chemistry, v.61, no.16, pp.7218 - 7233 Journal of Medicinal Chemistry 61 16 7218 7233 N scie scopus 000442960800017 2-s2.0-85050633648 Chemistry, Medicinal Pharmacology & Pharmacy Article PROTEIN-COUPLED RECEPTORS SEROTONIN RECEPTOR MOLECULAR-CLONING CRYSTAL-STRUCTURE STRUCTURAL BASIS CAMP PRODUCTION DRUG DISCOVERY SLEEP AGONIST BINDING serotonin receptor biased ligand 5-HT7R GPCR EEG