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