DEVELOPMENT OF CORTICOTROPIN-RELEASING FACTOR ANTAGONISTS

CORTICOTROPIN-RELEASING FACTOR (CRF), A 41-AMINO ACID PEPTIDE, ACTING AT SPECIFIC RECEPTORS IN THE BRAIN AND PITUITARY HAS BEEN DEMONSTRATED TO INITIATE BEHAVIORAL, PHYSIOLOGICAL AND NEUROENDOCRINE RESPONSES THAT MIMIC THE RESPONSE TO STRESS IN ANIMALS. IN ADDITION TO ITS PHYSIOLOGICAL ROLE IN MEDIATING STRESS, RECENT CLINICAL STUDIES HAVE PROVIDED EVIDENCE TO SUGGEST THAT HYPERACTIVITYOF CRF-CONTAINING PATHWAYS WITHIN THE BRAIN MAY BE A CONTRIBUTING PATHOPHYSIOLOGIC FACTOR IN DEPRESSIVE DISORDERS. HYPERSECRETION AND/OR HYPERPRODUCTION OF CRF HASALSO BEEN IMPLICATED IN A NUMBER OF OTHER STRESS-RELATED DISORDERS INCLUDING ANXIETY, STRESS-INDUCED CARDIOVASCULAR ABNORMALITIES, ANOREXIA NERVOSA AND IRRITABLE BOWEL SYNDROME. THE CURRENT PROPOSAL PROVIDES A PLAN FOR IDENTIFICATION AND EVALUATION OF CENTRALLY-ACTIVE NONPEPTIDE ANTAGONISTS OF CRF TO BE DEVELOPED AS NOVEL THERAPEUTIC APPROACHES FOR TREATING ANY OF THE DISORDERS MENTIONED ABOVE. STARTING WITH AN INVENTORY OF APPROXIMATELY 20,000 COMPOUNDS, IN VITRO RADIOLIGAND BINDING AND ADENYLATE CYCLASE ASSAYS WILL SERVE AS INITIAL SCREENING PROCEDURES FOR IDENTIFYING SELECTIVE CRF ANTAGONISTS. LEAD STRUCTURES WILL THEN BE EVALUATED FOR CRF-ANTAGONIST ACTIVITY IN VIVO USING BOTH BEHAVIORAL AND CARDIOVASCULAR MONITORING. FINALLY, CRF-ANTAGONISTS WILL BE EVALUATED FOR ANXIOLYTIC POTENTIAL IN A BATTERY OF BEHAVIORAL TESTS. COMPOUNDS IDENTIFIED DURING PHASE I STUDIES WILL PROVIDE POINTS OF DEPARTURE FOR SYNTHETIC CHEMICAL IMPROVEMENTS DURING PHASE II WORK WITH CONTINUED EVALUATION OF COMPOUNDS FOR ANXIOLYTIC ACTIVITY AS WELL AS THE DEVELOPMENT OF ADDITIONAL ANIMAL MODELS TO ASSESS OTHER POTENTIAL THERAPEUTIC USES FOR A CRF ANTAGONIST.