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 β-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.
Bibliographical noteFunding Information:
We are grateful to the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (contract: HHSN-271-2008-00025-C) for providing binding affinity data. This research is supported by the Original Technology Research Program (NRF-2016M3C7A1904344) and the Basic Science Research Program (NRF-2021R1A2C2006244) funded by the National Research Foundation of Korea (NRF). In addition, this work is additionally funded by the Korea Institute of Science and Technology (KIST) Institutional Program (2E30961 and 2E30960).
© 2021 American Chemical Society.
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery