SELECTIVE CRF ANTAGONISTS FOR BOWEL DISORDERS

Corticotropin releasing factor (CRF) controls the anterior pituitary secretion of adrenocorticotropin and other propiomelanocortin products. CRF also coordinates the endocrine, behavioral and
autonomic responses to stress. The long-term objectives of this proposal are to
establish that selective corticotrophin releasing factor receptor subtype 1
(CRF1) antagonists will have therapeutic implications in irritable bowel
syndrome (IBS) characterized by altered bowel movement and visceral
hypersensitivity. The specific aims will be: 1) to demonstrate specific tissue
localization of CRF1 receptors in the colon; 2) to identify and synthesize
centrally acting vs. peripherally acting high affinity CRF1 receptor
non-peptide antagonists; and 3) to examine both centrally acting and
peripherally acting CRF1 antagonists in models of stress-related colonic motor
stimulation and visceral hypersensitivity in rodents for potential utility in
IBS. This will be achieved using novel tools including C-terminal CRF1 receptor
antibodies, selective CRF1 receptor antagonists and experimental models to
assess distal colonic motor function and visceromotor response to colorectal
distension. Based on the co-morbidity between anxiety/depression and IBS and
stress-related onset or enhanced IBS symptomatology, these pre-clinical studies
will provide the key information needed to pursue a novel therapeutic approach
for IBS using Neurocrine CRF1 receptor antagonists and to