Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 16, Pages 7218-7233Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00642
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Funding
- US National Institute of Mental Health (NIMH) [HHSN-271-2008-00025-C]
- Original Technology Research Program - National Research Foundation of Korea (NRF) [NRF-2016M3C7A1904344, 2016M3C7A1904343]
- Korea Institute of Science and Technology (KIST) [2E27870, 2E28412]
- National Research Foundation of Korea [2016M3C7A1904343, 2016M3C7A1904344] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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/beta-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 beta-arrestin signaling pathways, 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine 1g was discovered as the beta-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.
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