E-6837 is a novel, selective and high-affinity
5-HT(6) receptor ligand (pK(i): 9.13) which in vitro demonstrates partial agonism at a presumably silent rat
5-HT(6) receptor and full agonism at a constitutively active human
5-HT(6) receptor by monitoring the cAMP signaling pathway.The effects of chronic treatment with
E-6837 were determined in diet-induced obese (DIO)-rats on changes in
body weight, food and water intake, plasma indices of comorbid risk factors, and weight regain on compound withdrawal. The centrally acting
antiobesity drug,
sibutramine, was used as the reference comparator. Sustained
body weight loss and decreased cumulative food intake of DIO-rats was observed with
E-6837 (30 mg kg(-1), p.o., twice a day) during the 4-week treatment period. The onset of the
E-6837 effect on
body weight was slower than that of
sibutramine (5 mg kg(-1), p.o.), while its maximal effect was greater, that is -15.7 versus -11.0%.E-6837-induced
weight loss was exclusively mediated by a decrease (31.7%) in fat mass, with a concomitant reduction (49.6%) in plasma
leptin. Reduced
obesity was also reflected in improved
glycemic control. Although weight regain occurred after withdrawal from either compound, the
body weights after
E-6837 (-6.6%) remained lower than after
sibutramine (-3.8%) indicating that the greater efficacy of the former did not result in profound rebound
hyperphagia/
weight gain. These results show that the
5-HT(6) receptor partial agonist,
E-6837, is a promising new approach to the management of
obesity with the potential to produce greater sustained
weight loss than
sibutramine.