High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy.
Sci Adv
; 4(10): eaav1966, 2018 10.
Article
en En
| MEDLINE
| ID: mdl-30402545
ABSTRACT
How appetite is modulated by physiological, contextual, or pharmacological influence is still unclear. Specifically, the discovery of appetite modulators is compromised by the abundance of side effects that usually limit in vivo drug action. We set out to identify neuroactive drugs that trigger only their intended single behavioral change, which would provide great therapeutic advantages. To identify these ideal bioactive small molecules, we quantified the impact of more than 10,000 compounds on an extended series of different larval zebrafish behaviors using an in vivo imaging strategy. Known appetite-modulating drugs altered feeding and a pleiotropy of behaviors. Using this multibehavioral strategy as an active filter for behavioral side effects, we identified previously unidentified compounds that selectively increased or reduced food intake by more than 50%. The general applicability of this strategy is shown by validation in mice. Mechanistically, most candidate compounds were independent of the main neurotransmitter systems. In addition, we identified compounds with multibehavioral impact, and correlational comparison of these profiles with those of known drugs allowed for the prediction of their mechanism of action. Our results illustrate an unbiased and translational drug discovery strategy for ideal psychoactive compounds and identified selective appetite modulators in two vertebrate species.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Apetito
/
Depresores del Apetito
/
Conducta Animal
/
Estimulantes del Apetito
/
Descubrimiento de Drogas
/
Ensayos Analíticos de Alto Rendimiento
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Límite:
Animals
Idioma:
En
Revista:
Sci Adv
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos