Discovery of β-Arrestin Biased Ligands of 5-HT7R

Title
Discovery of β-Arrestin Biased Ligands of 5-HT7R
Authors
이재균임혜원추현아성지혜김영재이지언김형국민선준태진성이현주
Keywords
serotonin receptor; biased ligand; 5-HT7R; GPCR; EEG
Issue Date
2018-08
Publisher
Journal of medicinal chemistry
Citation
VOL 61, NO 16-7233
Abstract
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.
URI
http://pubs.kist.re.kr/handle/201004/68075
ISSN
0022-2623
Appears in Collections:
KIST Publication > Article
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