Antiobesity effect of YM348, a novel 5-HT2c receptor agonist, in Zucker rats

The purpose of the present study was to investigate the potency of (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine (YM348), a 5-HT2C receptor agonist, as an antiobesity agent in Zucker rats. Single oral administration of YM348 at 0.1, 0.3, 1 and 3 mg/kg significantly reduced food intake in a dose-dependent manner. Thin effect of YM348 on food intake was inhibited by SB242084, a selective 5-HT2C receptor antagonist. In addition, single administration of YM348 significantly increased body temperature and calorie expenditure at doses of 0.3, 1 and 3 mg/kg, and 1 and 3 mg/kg p.o., respectively. The increasing effect of YM348 on body temperature and calorie expenditure was inhibited by SB242084. Chronic subcutaneous infusion of YM348 (3 and 30 mg/kg/day) for 2 weeks also decreased food intake. However, this hypophagic effect of YM348 was marked during the initial week of infusion but only minor in the second. In contrast, no diminution of effect on body temperature and calorie expenditure was seen on repeated administration of YM348 (1 mg/kg p.o.). Two weeks' subcutaneous infusion of YM348 (3 and 30 mg/kg/day) resulted in a significant decrease in body weight gain throughout the experiment. These results suggest that the maintenance of thermogenesis contributed to the reduced body weight by YM348. The ability of YM348 to decrease body weight in Zucker rats suggests its strong potential for development as an antiobesity agent in humans. (C) 2004 Elsevier B.V. All rights reserved.