Corticotropin releasing factor (CRF) and its related peptide urocortin coordinate the overall response of the body to stress and are involved in CNS and peripheral disease states. Two CRF receptor subtypes (CRF1 and CRF2 receptors) which share approx. 70 percent sequence identity have recently been cloned and demonstrated to have distinct brain and peripheral localizations and unique pharmacological profiles. For the CRF2 receptor, at least two splice forms with different 5'-coding sequences (CRF2alpha and CRF2beta) have been identified. In Phase I studies designed to understand the relevance of the novel CRF2 receptor to the physiological and pathological actions of CRF/urocortin, we cloned and characterized the human equivalent of the CRF2 receptor, established stable cell lines expressing the rat and human CRF2 receptor, screened in a high throughput screening assay and identified lead heterocyclic molecules (MW<500). In addition, our localization and preliminary animal studies suggest that the CRF1 receptor regulates the endocrine, anxiogenic, arousal and learning and memory effects of CRF/urocortin. The CRF2alpha receptor is neuronally localized and mediates the anorectic effects of CRF and urocortin; selective CRF2 receptor antagonists may be useful for the treatment of anorexia nervosa which is associated with hypersecretion of CRF in brain. The CRF2beta receptor is present on cerebral pial arterioles which have been implicated in migraine; microapplication of CRF, urocortin and related peptides increasae pial arteriolar diameter suggesting that CRS2 receptor antoagonists may be useful for treatment of migraine. The major goals of the Phase II proposal are to screen additional chemical libraries and to design and synthesize orally active, high affinity CRF2 receptor antagonists which possess optimal weight enhancing and vascular regulation properties with acceptable side effect and safety profiles for the treatment of anorexia nervosa and migraine, respectively. This will be accomplished through a combination of rational drug design and combinatorial chemistry techniques to optimize lead molecules for in vitro activity and selectivity at the CRF2 receptor and in vivo activity in a variety of animal models relevant to the therapeutic indications.
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