NOVEL APPETITE SUPPRESSANTS: DISCOVERY AND DEVELOPMENT

THE SEARCH FOR A PHARMACOLOGICAL AGENT THAT WILL FACILITATE WEIGHT REDUCTION REMAINS AS ONE OF THE MOST CHALLENGING AREAS OF DRUG DEVELOPMENT. ANIMAL AND HUMAN DATA PROVIDE SOUND EVIDENCE THAT BODY WEIGHT IS REGULATED AROUND A PHYSIOLOGICAL "SET POINT," AND TO DATE THOSE THERAPEUTIC APPROACHES THAT HAVE ATTEMPTED TO ALTER AN ESTABLISHED SET POINT HAVE GENERALLY BEEN UNSUCCESSFUL. THIS PROPOSAL DESCRIBES AN OVERALL STRATEGY TO IDENTIFY AND DEVELOP NOVEL APPETITE SUPPRESSANTS. A BROAD-BASED RECEPTOR SCREENING APPROACH WILL BE EMPLOYED TO IDENTIFY POTENTIAL ANORECTIC DRUGS ON THE BASIS OF THEIR POTENCIES AT SPECIFIC RECEPTORS OF THOSE NEUROPEPTIDES KNOWN TO BE INTIMATELY INVOLVED IN THE REGULATION OF FEEDING AND BODY WEIGHT. THESE PUTATIVE ANORECTICS WILL BE PHARMACOLOGICALLY CHARACTERIZED BY THEIR EFFECTS ON FEEDING AS EVALUATED IN A VARIETY OF PARADIGMS. WHEN APPROPRIATE, ACTIONS OF THESE DRUGS ON OTHER PHYSIOLOGICAL ASPECTS OF FEEDING WILL ALSO BE DETERMINED. PHASE I SUPPORT IS REQUESTED TO PROVIDE FUNDS FOR THE INITIAL RECEPTOR SCREENING AND DETERMINATION OF APPETITE SUPPRESSANT ACTIVITY IN VIVO. THOSE COMPOUNDS WHICH DEMONSTRATE IN VITRO POTENCY AT THE RECEPTORS OF INTEREST AND IN VIVO POTENCY AND EFFICACY TO REDUCE FOOD INTAKE AND BODY WEIGHT WILL BE EXTENSIVELY EVALUATED (PHASE II) FOR HORMONAL EFFECTS, METABOLIC RESPONSES, OTHER UNTOWARD SIDE EFFECTS AND TOXICITY.