Discovery of beta-Arrestin Biased Ligands of 5-HT7R

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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.
Publisher
AMER CHEMICAL SOC
Issue Date
2018-08
Language
English
Article Type
Article
Keywords

PROTEIN-COUPLED RECEPTORS; SEROTONIN RECEPTOR; MOLECULAR-CLONING; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; CAMP PRODUCTION; DRUG DISCOVERY; SLEEP; AGONIST; BINDING

Citation

JOURNAL OF MEDICINAL CHEMISTRY, v.61, no.16, pp.7218 - 7233

ISSN
0022-2623
DOI
10.1021/acs.jmedchem.8b00642
URI
http://hdl.handle.net/10203/245928
Appears in Collection
EE-Journal Papers(저널논문)
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