Lee, Ji eon KWAG, RINA Lee, S. Doyoung, Kim Woo, Ji Wan Cho, Yak dol Kim, H.J. Kim, Jeong jin Jeon, Byungsun Choo, Hyun ah 2024-01-19T14:33:09Z 2024-01-19T14:33:09Z 2021-09-02 2021-06 0022-2623 https://pubs.kist.re.kr/handle/201004/116958 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. ？ 2021 American Chemical Society. English American Chemical Society Discovery of G Protein-Biased Ligands against 5-HT7R Article 10.1021/acs.jmedchem.1c00110 1 Journal of Medicinal Chemistry, v.64, no.11, pp.7453 - 7467 Journal of Medicinal Chemistry 64 11 7453 7467 N scie scopus 000662187100023 2-s2.0-85108021367 Chemistry, Medicinal Pharmacology & Pharmacy Article actin binding protein biphenyl biphenyl derivative G protein coupled receptor isoprotein ligand nerve protein serotonin 7 receptor serotonin receptor Shank3 protein, mouse animal animal behavior chemistry drug effect drug stability genetics half life time human Institute for Cancer Research mouse male metabolism microsome mouse preclinical study structure activity relation transgenic mouse Animals Behavior, Animal Biphenyl Compounds Drug Evaluation, Preclinical Drug Stability Half-Life Humans Ligands Male Mice Mice, Inbred ICR Mice, Transgenic Microfilament Proteins Microsomes Nerve Tissue Proteins Protein Isoforms Receptors, G-Protein-Coupled Receptors, Serotonin Structure-Activity Relationship G protein-biased ligand GPCR 5-HT7R autism spectrum disorder stereotypy