Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening.
Proc Natl Acad Sci U S A
; 109(1): 101-6, 2012 Jan 03.
Article
en En
| MEDLINE
| ID: mdl-22184224
ABSTRACT
The circadian clock coordinates daily oscillations of essential physiological and behavioral processes. Conversely, aberrant clocks with damped amplitude and/or abnormal period have been associated with chronic diseases and aging. To search for small molecules that perturb or enhance circadian rhythms, we conducted a high-throughput screen of approximately 200,000 synthetic compounds using Per2lucSV reporter fibroblast cells and validated 11 independent classes of molecules with Bmal1luciferase reporter cells as well as with suprachiasmatic nucleus and peripheral tissue explants. Four compounds were found to lengthen the period in both central and peripheral clocks, including three compounds that inhibited casein kinase Iε in vitro and a unique benzodiazepine derivative acting through a non-GABA(A) receptor target. In addition, two compounds acutely induced Per2lucSV reporter bioluminescence, delayed the rhythm, and increased intracellular cAMP levels, but caused rhythm damping. Importantly, five compounds shortened the period of peripheral clocks; among them, four compounds also enhanced the amplitude of central and/or peripheral reporter rhythms. Taken together, these studies highlight diverse activities of drug-like small molecules in manipulating the central and peripheral clocks. These small molecules constitute a toolbox for probing clock regulatory mechanisms and may provide putative lead compounds for treatment of clock-associated diseases.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ensayos Analíticos de Alto Rendimiento
/
Relojes Circadianos
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Límite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos