Discovery of ß-Arrestin Biased Ligands of 5-HT7R.
J Med Chem
; 61(16): 7218-7233, 2018 08 23.
Article
en En
| MEDLINE
| ID: mdl-30028132
ABSTRACT
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/ß-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 ß-arrestin signaling pathways, 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4- d]azepine 1g was discovered as the ß-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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sueño
/
Azepinas
/
Receptores de Serotonina
/
Beta-Arrestinas
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2018
Tipo del documento:
Article