THE PREVALENCE OF OBESITY IN THE U.

THE PREVALENCE OF OBESITY IN THE U.S. POPULATION (26% OF PEOPLE IN ALL AGE GROUPS) AND ITS INCREASED RISK FOR LIFE- THREATENING OR CHRONIC DISEASES, SUCH AS CANCER, HYPER- TENSION, AND HEART DISEASE, HAVE CAUSED THE NIH IN 1985 TO DECLARE OBESITY A DISEASE. UNFORTUNATELY, PREDICTABLE PHARMACOLOGIC MEANS FOR LONG-TERM WEIGHT REDUCTION ARE STILLLACKING DESPITE A LARGE NUMBER OF AVAILABLE DRUGS. SUCH DRUGS, PRIMARILY OF THE AMPHETAMINE CLASS, HAVE BEEN SHOWN TO PROVIDE ONLY MODEST WEIGHT REDUCTION OVER THE SHORT TERM.IN ADDITION, THEIR EFFECTIVENESS IS MITIGATED BY REBOUND EATING, ABUSE, AND ADDICTION. THE NEUROPHARMACOLOGY OF APPETITE AND SATIETY ARE JUST BEGINNING TO BE UNDERSTOOD AT THE MOLECULAR LEVEL, AND THE NUMBER OF POTENTIAL PHARMACO- LOGIC MEANS TO ALTER FEEDING BEHAVIOR HAS INCREASED ACCORD- INGLY. ENHANCEMENT OF APPETITE BY NEWLY DISCOVERED NEURO- PEPTIDES, FOR EXAMPLE, MUST AWAIT THE DISCOVERY OF BIOAVAILABLE NONPEPTIDE AGENTS. OF SEVERAL CENTRAL MECHANISMS FOR CONTROLLING APPETITE AND FEEDING, THERE IS CONSIDERABLE EVIDENCE THAT THE OPIOID SYSTEM PLAYS A MAJOR ROLE. THE EXPANDING BODY OF PHARMACOLOGICAL DATA PERTAININGTO OPIATES SUGGESTS A CLEAR NOVEL APPROACH TO A SAFE APPETITE SUPPRESSANT. SEVERAL EXISTING OPIATE ANTAGONISTS INHIBIT FEEDING, ALTHOUGH THE AVAILABLE ONES MAY PRODUCE ANYCOMBINATION OF SHORT ACTION, TOLERANCE, OR DYSPHORIA. HOWEVER, AS INDIVIDUAL ANTAGONISTS HAVE ONE OR ANOTHER USEFUL PROPERTY, THE DESIGN OF OPIATE ANTAGONISTS WITH SUPERIOR CHARACTERISTICS SHOULD BE POSSIBLE. INFORMED BY STRATEGIES FROM OPIATE RECEPTOR PHARMACOLOGY, NOVA IS IN THEPROCESS OF SYNTHESIZING A SERIES OF NOVEL OPIATE ANTAGONISTSLED BY A PROPRIETARY COMPOUND DESIGNATED NPC-168. PHASE I SUPPORT WILL ESTABLISH AND CARRY OUT MOLECULAR PHARMACOLOGY AND FEEDING TRIALS OF SEVERAL SUCH COMPOUNDS, WHICH WILL BE AVAILABLE FOR EVALUATION FOR THE PHASE I GRANT PERIOD. SUCCESSFUL COMPOUNDS THAT PASS THIS SCREEN WILL THEN BE MOREVIGOROUSLY EVALUATED (PHASE II) FOR SUCH PARAMETERS AS TOLERANCE, METABOLIC ALTERATIONS, AND ACUTE AND CHRONIC TOXICITY.