Discovery of β‑Arrestin Biased Ligands of 5‑HT₇R

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/β-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 β-arrestin signaling
pathways, 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo­[3,4-d]­azepine 1g was discovered as the β-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.