NOVEL HYPOGLYCEMIC AGENTS FROM DIOSCOREA SPP.

THE OBJECTIVE OF THIS PROJECT IS TO IDENTIFY AND EVALUATE NOVEL HYPOGLYCEMIC AGENTS OBTAINED FROM A PLANT USED IN FOLKMEDICINE. THE LONG-TERM GOAL IS TO ISOLATE AND STRUCTURALLYCHARACTERIZE ONE OR MORE NATURAL PRODUCTS WITH HYPOGLYCEMIC ACTIVITY HAVING NOVEL STRUCTURES AND POSSIBLE NOVEL MECHANISMS OF ACTION, FROM WHICH ANALOG EXHIBITING REDUCED TOXICITY AND ENHANCED EFFICACY CAN BE DEVELOPED AND ENTERED INTO CLINICAL TRIALS. IN PHASE I, EMPHASIS WILL BE PLACED ON EVALUATING THE MECHANISMS OF ACTION AND TOXICITY OF DIOSCORETINE AND ITS STRUCTURAL CONGENERS, ALKALOIDS ISOLATED FROM THE ROOTS OF DIOSCOREA DUMETORUM, A MEMBER OF THE YAM FAMILY (DIOSCOREACEAE). THIS COMPOUND HAS BEEN PREVIOUSLY ISOLATEDAND STRUCTURALLY CHARACTERIZED, AND HAS BEEN SHOWN TO EXHIBIT POTENT HYPOGLYCEMIC ACTIVITY IN NORMAL, GLUCOSE-CHALLENGED, AND ALLOXANIZED DIABETIC ANIMALS. THE RESEARCH WILL FOCUS ON FURTHER MECHANISTIC AND TOXICOLOGICAL EVALUATIONS OF DISCORETINE AND ITS NATURALLY OCCURRING CONGENERS IN VARIOUS ANIMAL MODELS OF NON-INSULIN-DEPENDENT DIABETES AND ON THE DEVELOPMENT AND EVALUATION OF SEMISYNTHETIC AND SYNTHETIC ANALOGS IN THE SAME ANIMAL MODELS.