Vol. 287, Issue 1, 122-127, October 1998

The Selective Norepinephrine Reuptake Inhibitor, LY368975, Reduces Food Consumption in Animal Models of Feeding

Donald R. Gehlert, Laura Dreshfield, Frank Tinsley, Mark J. Benvenga, Scott Gleason, Ray W. Fuller, David T. Wong and Susan K. Hemrick-Luecke

Neuroscience and Endocrine Research, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana

The compound, LY368975 ((R)-thionisoxetine) is a potent and selective inhibitor of the norepinephrine (NE) reuptake site. We evaluated the in vivo properties of LY368975 in various animal models. In mice, LY368975 prevented heart NE depletion by 6-hydroxydopamine with an ED₅₀ of 1.22 mg/kg. In rats, orally administered LY368975 inhibited ³H-NE uptake into hypothalamic synaptosomes ex vivo with an ED₅₀ of 2.5 mg/kg and ³H-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, LY368975 produced a dose-dependent reduction in consumption with a 44% decrease at 3 mg/kg. At doses up to 10 mg/kg p.o., LY368975 produced no significant effects on locomotor activity suggesting the compound does not activate or sedate the animals at pharmacologically relevant doses. Therefore, LY368975 is an orally available and centrally active NE reuptake inhibitor that is capable of reducing food consumption in rodents. Compounds of this class may have use in the treatment of obesity and eating disorders.