The histamine H3 receptor (H3R) is a constitutively active GPCR, and both inverse agonists and neutral antagonists have been identified. The potential for specific therapeutic utility for these classes of antagonists has not yet been fully explored. In the present studies, compounds were characterized as inverse agonists or neutral antagonists based on differential H3R binding properties. Both classes were evaluated for their ability to reduce food intake in acute and subchronic paradigms. GT-2016, GT-2231, GT-2349, and GT-2394 were identified as inverse agonists, while GT-2227, GT-2331, GT-2355, and GT-2390 were identified as neutral antagonists. CNS penetration profiles were determined for each compound, and effects on acute food intake were evaluated at doses which provided maximal CNS H3R occupancy. Acute i.p. treatment with H3R inverse agonists produced a time-dependent decrease in food intake over a 24-h time-course, with no effect on water intake. The H3R neutral antagonists had no effect on food and water intake. GT-2394 was further evaluated in several subchronic dosing paradigms. Weight gain was evaluated in normal male Sprague-Dawley rats and obese male Zucker rats. Rats were administered a single dose of 3 mg/kg or 10 mg/kg (p.o.) once per day for 15 days. GT-2394 produced a significant decrease in food intake and body weight gain over the treatment period. These data suggest that H3R inverse agonists may represent a novel class of compounds for development as appetite suppressants.