Corticotropin releasing factor (CRF), a 41 amino acid peptide, controls the anterior pituitary secretion of adrenocorticotropin and other proopiomelanocortin products. CRF also coordinates the endocrine, behavioral and autonomic responses to stress. Considerable evidence exists from studies of cerebrospinal fluid, postmortem tissue receptor measurements, and CRF stimulation tests to support the hypothesis that CRF is hypersecreted in clinically depressed patients. There is also evidence for an involvement of CRF in the pathophysiology of anxiety disorders and in the mechanism of action of benzodiazepine and non- benzodiazepine anxiolytics. Neurocrine has developed proprietary small molecule CRF-receptor antagonists. The goal of this proposal is to systematically delineate the important structural characteristics of these molecules which are responsible for binding to the CRF receptor, and to discover additional derivatives. Combinatorial libraries of small molecule analogues will be prepared and investigated for their in vitro potency at the human CRF-receptor. The recent cloning of the human CRF receptor allows for novel biological assay formats to be developed which will greatly enhance the identification of novel, small molecule orally active drugs for the treatment of depression and anxiety disorders.
