Discovery of β-Arrestin Biased Ligands of 5-HT7R
- Discovery of β-Arrestin Biased Ligands of 5-HT7R
- 이재균; 임혜원; 추현아; 성지혜; 김영재; 이지언; 김형국; 민선준; 태진성; 이현주
- serotonin receptor; biased ligand; 5-HT7R; GPCR; EEG
- Issue Date
- Journal of medicinal chemistry
- VOL 61, NO 16-7233
- 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/β-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 β-arrestin signaling pathways, 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine 1g was discovered as the β-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.
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