Pharmacological evaluation of a novel corticotropin-releasing factor 1 receptor antagonist T-3047928 in stress-induced animal models in a comparison with alosetron.

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.