Discovery of G Protein-Biased Ligands against 5-HT7R
- Authors
- Lee, Jieon; Kwag, Rina; Lee, Soyeon; Kim, Doyoung; Woo, Jiwan; Cho, Yakdol; Kim, Hak Joong; Kim, Jeongjin; Jeon, Byungsun; Choo, Hyunah
- Issue Date
- 10-6월-2021
- Publisher
- AMER CHEMICAL SOC
- Citation
- JOURNAL OF MEDICINAL CHEMISTRY, v.64, no.11, pp.7453 - 7467
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF MEDICINAL CHEMISTRY
- Volume
- 64
- Number
- 11
- Start Page
- 7453
- End Page
- 7467
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/127854
- DOI
- 10.1021/acs.jmedchem.1c00110
- ISSN
- 0022-2623
- Abstract
- There has been significant attention concerning the biased agonism of G protein-coupled receptors (GPCRs), and it has resulted in various pharmacological benefits. 5-HT7R belongs to a GPCR, and it is a promising pharmaceutical target for the treatment of neurodevelopmental and neuropsychiatric disorders. Based on our previous research, we synthesized a series of 6-chloro-2'-methoxy biphenyl derivatives 1, 2, and 3 with a variety of amine scaffolds. These compounds were evaluated for their binding affinities to 5-HTR subtypes and their functional selectivity toward the Gs protein and the beta-arrestin signaling pathways of 5-HT7R. Among them, 2-(6-chloro- 2'-methoxy-[1,1'-biphenyl]-3-yl)-N-ethylethan-1-amine, 2b, was found to be a G-protein-biased ligand of 5-HT7R. In an in vivo study with Shank3 transgenic mice, the self-grooming behavior test was performed with 2b, which increased the duration of self-grooming. The experiments further suggested that 5-HT7R is associated with autism spectrum disorders (ASDs) and could be a therapeutic target for the treatment of stereotypy in ASDs.
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