Molecular and Cellular Endocrinology, 2014, Volume: 393, Issue: 1-2, Pages: 120-128, DOI: 10.1016/j.mce.2014.06.003
M. Holubova, V. Nagelova, Z. Lacinova, M. Haluzik, D. Sykora, A. Moulin, A. L. Blayo, J. A. Fehrentz, J. Martinez, A. Stofkova, J. Jurcovicova, B. Zelezna, L. Maletinska
The only peripherally released orexigenic hormone, ghrelin, plays a key role in food intake and body wt. regulation. Antagonizing the ghrelin receptor, GHS-R1a, represents a promising approach for anti-obesity therapy. In our study, two novel GHS-R1a antagonists JMV4208 and JMV3002, which are trisubstituted 1,2,4-triazoles, decreased food intake in fasted lean mice in a dose-dependent manner, with ED50 values of 5.25 and 2.05 mg/kg, resp. Both compds. were stable in mouse blood, with half-lives of 90 min (JMV4208) and 60 min (JMV3002), and disappeared from the blood 8 h after administration. Fourteen days of treatment with the ghrelin antagonists (20 mg/kg twice a day) decreased food intake, body wt. and adipose tissue mass in mice with diet-induced obesity (DIO). These results are likely attributable to an impact on food intake redn. and an attenuated expression of the lipogenesis-promoting enzymes (acetyl-CoA carboxylase 1 in s.c. fat and fatty acid synthase in s.c. and i.p. fat). The decrease in fat mass neg. impacted circulating leptin levels. These data suggest that JMV4208 and JMV3002 could be useful therapeutic agents for the treatment of obesity.