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| Type |
Poster Presentation |
| Area |
Medicinal Chemistry |
| Room No. |
Grand Ballroom |
| Time |
10월 18일 (목요일) 11:00~12:30 |
| Code |
MEDI.P-282 |
| Subject |
Tetrahydroazepines as β-arrestin biased ligands of 5-HT7R |
| Authors |
Jieon Lee, Hyunah Choo1,*, Youngjae Kim2
Center for Neuromedicine, Korea Institute of Science and Technology, Korea
1Korea Institute of Science and Technology, Korea
2Department of Chemistry, Yonsei University, Korea
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| Abstract |
5-HT7 receptor (5-HT7R) is the most recently described member of the 5-HT receptor family. Autoradiographic and immunohistochemisry studies in human, guinea pig, and rat CNS showed that 5-HT7R is distributed in discrete areas with high to moderate concentration in limbic areas, such as the thalamus, hypothalamus, hippocampus, and amygdala, in the raphe and cortical regions. On the basis of its distribution in the CNS, 5-HT7R was proposed to be involved in important roles such as circadian rhythm, sleep, learning and memory well as several diseases such as migraine, sleep disturbance, and depression. 5-HT7R belongs to the family of G protien coupled receptors(GPCRs) and is shown to be positively coupled to adenylate cyclase through activation of Gs-proteins. Particularly, not only G proteins but also non-G protein effectors such as β-arrestin are involved in GPCR signaling. The so-called “functionally selective” or “biased” ligands are believed to stimulate either G protein signaling pathway or β-arrestin signaling pathway independently. 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. Herein, we designed and synthesized tetrahydroazepine derivatives 1 and 2 with arylpyrazolo moiety or aryisoxazolo moiety. Through several biological evaluations such as binding affinity, selectivity profile, and functions in G protein and β-arrestin signaling pathways, tetrahydroazepine derivative 1g was discovered as the β-arrestin biased ligand of 5-HT7R. In addtion, we evaluated the effect of 1g on electroencephalogram (EEG) sleep architecture to investigate a correlation between β-arrestin biased activity of 1g and NREM/REM sleep pattern in mice. |
| E-mail |
h16508@kist.re.kr |
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122nd General Meeting of the KCS