Corticotropin releasing factor receptor antagonists: potential future therapy in gastroenterology?

New corticotropin releasing factor (CRF) antagonists in irritable bowel disease (IBS) warrant testing, and CRF1 receptors may be a promising target for the treatment of IBS Recent years have witnessed important developments in the understanding of the biochemical coding of stress.1 In addition to the 41 amino acid peptide, corticotropin releasing factor (CRF), novel mammalian CRF related peptides, urocortin 1, urocortin 2, and urocortin 3 have recently been discovered.2 These CRF ligands display distinct affinity to the two cloned G protein coupled CRF 1 (CRF1) and 2 (CRF2) receptors.1–3 CRF has higher affinity for CRF1 than for CRF2 receptor, urocortin 1 displays equal affinity for both subtypes, and urocortin 2 and 3 have selective affinity for CRF2 receptor.2,3 In addition to the mapping of CRF ligands and receptors in the brain2,4 and gut,5–7 the development of potent selective CRF1 and CRF2 antagonists8,9 and generation of transgenic mouse models1 provided tremendous insight in the investigation of the underlying mechanisms of stress. Convergent studies established the role of the brain CRF-CRF1 pathways in mediating the endocrine, autonomic, behavioural, and visceral responses to stress1,3,10,11 while CRF2 receptors may be important in dampening stress sensitivity.1 Extensive preclinical research effort has solidified the concept that overactivity in the brain CRF-CRF1 signalling system contributes to the onset of anxiety disorders and depression.12 These observations have spurred the development of a number of non-peptide CRF1 receptor antagonists which can readily cross the blood-brain barrier on peripheral administration.8,9 These compounds prevent various stress related anxiogenic behaviours in rodents.1,13 Clinical studies in patients with major depression and post-traumatic disorders showed that CRF levels are …