THE SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITOR, LY368975, REDUCES FOOD-CONSUMPTION IN ANIMAL-MODELS OF FEEDING

The compound, LY368975 ((R)-thionisoxetine) is a potent and selective inhibitor of the norepinephrine (NE) reuptake site. We evaluated the i n vivo properties of LY368975 in various animal models. In mice, LY368 975 prevented heart NE depletion by 6-hydroxydopamine with an ED50 of 1.22 mg/kg. In rats, orally administered LY368975 inhibited H-3-NE upt ake into hypothalamic synaptosomes ex vivo with an ED50 of 2.5 mg/kg a nd H-3-tomoxetine binding to the NE transporter with an ED50 of 2.7 mg /kg. When rats were deprived of food for 18 hr, 10 mg/kg LY368975 was able to suppress food intake 1, 2 and 4 hr after reintroduction of the feed. In nonfasted rats trained to drink sweetened condensed milk, LY 368975 produced a dose-dependent reduction in consumption with a 44% d ecrease at 3 mg/kg. At doses up to 10 mg/kg p.o., LY368975 produced no significant effects on locomotor activity suggesting the compound doe s not activate or sedate the animals at pharmacologically relevant dos es. Therefore, LY368975 is an orally available and centrally active NE reuptake inhibitor that is capable of reducing food consumption in ro dents. Compounds of this class may have use in the treatment of obesit y and eating disorders.