Orphan endocrine disorders such as Cushing's disease and Congenital Adrenal Hyperplasia are marked by elevated levels of glucocorticoids as a consequence of elevated serum ACTH. Currently, no useful ACTH antagonists exist and no non-peptide drugs have been described that act at this site. We will utilize a high throughput colorimetric screening system based on the cloned human ACTH-R and combinatorial compound libraries to identify ACTH-R antagonists. Antagonists that act at the ACTH receptor may be very useful in the study of the H-P-A axis. and may have clinical utility as well. Drugs currently used to treat ACTH disorders have negative side-effects including: hepatic necrosis, anorexia, nausea, vomiting, and skin rashes. In many cases surgery is the only alternative. It would be highly beneficial to develop compounds that block adrenocortical steroidogenesis by patently and specifically antagonizing ACTH action.Proposed commercial application:Drugs which treat disorders such as Cushing's disease and Congenital Adrenal Hyperplasia are estimated as a $l00 million market. This assay would allow for much more rapid development of lower toxicity pharmaceuticals for these and other ACTH related diseases. ACTH antagonists may also be useful for the reduction of hypercortisolemia often seen in depression and this would constitute a much larger market.National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
