Pharmacological evaluation of a novel corticotropin-releasing factor 1 receptor antagonist T-3047928 in stress-induced animal models in a comparison with alosetron.
Neurogastroenterol Motil
; 32(5): e13795, 2020 05.
Article
em En
| MEDLINE
| ID: mdl-31970891
ABSTRACT
BACKGROUND:
The major symptoms of irritable bowel syndrome (IBS) are changes in bowel habits and abdominal pain. Psychological stress is the major pathophysiological components of IBS. Corticotropin-releasing factor (CRF) is a well-known integrator in response to psychological stress. In this study, a novel CRF1 receptor antagonist T-3047928 was evaluated in stress-induced IBS models of rats to explore its potency for IBS.METHODS:
Plasma adrenocorticotropic hormone (ACTH) levels after intravenous oCRH challenge were measured as a pharmacodynamic marker. Efficacies of oral T-3047928 were compared with oral alosetron, a 5-HT3 antagonist, on conditioning fear stress (CFS)-induced defecation, restraint stress (RS)-induced acute visceral pain, specific alteration of rhythm in temperature (SART) stress-induced chronic visceral pain, and normal defecation.RESULTS:
T-3047928 (1-10 mg/kg, p.o.) demonstrated a dose-dependent inhibition on oCRH-induced ACTH secretion. In disease models, T-3047928 suppressed fecal pellet output induced by CFS and improved both acute and chronic visceral hypersensitivity induced by RS and SART stress, respectively. Alosetron was also efficacious in stress-induced defecation and visceral pain models at 1 and 10 mg/kg, respectively. Alosetron, however, also suppressed normal defecation at lower those. On the other hand, T-3047928 did not change normal defecation even at higher dose than those in disease models.CONCLUSION:
T-3047928 is an orally active CRF1 antagonist that demonstrated potent inhibitory effects in stress-associated IBS models with no effect on normal defecation. Therefore, it is suggested that T-3047928 may have a potency as a novel option for IBS-D therapy with minimal constipation risk.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estresse Psicológico
/
Carbolinas
/
Receptores de Hormônio Liberador da Corticotropina
/
Síndrome do Intestino Irritável
/
Agonistas do Receptor 5-HT3 de Serotonina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Neurogastroenterol Motil
Assunto da revista:
GASTROENTEROLOGIA
/
NEUROLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Japão