Triazole GHS-R1a antagonists JMV4208 and JMV3002 attenuate food intake, body weight, and adipose tissue mass in mice
Language English Country Ireland Media print-electronic
Document type Journal Article
PubMed
24953973
DOI
10.1016/j.mce.2014.06.003
PII: S0303-7207(14)00177-4
Knihovny.cz E-resources
- Keywords
- Diet-induced obesity, Food intake, GHS-R1a antagonists, JMV3002, JMV4208, Male C57BL/6 mice,
- MeSH
- Picolinic Acids chemistry pharmacology MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Eating drug effects MeSH
- Receptors, Ghrelin antagonists & inhibitors MeSH
- Body Weight drug effects MeSH
- Triazoles chemistry pharmacology MeSH
- Adipose Tissue drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- JMV3002 MeSH Browser
- JMV4208 MeSH Browser
- Picolinic Acids MeSH
- Receptors, Ghrelin MeSH
- Triazoles MeSH
The only peripherally released orexigenic hormone, ghrelin, plays a key role in food intake and body weight 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, respectively. Both compounds were stable in mouse blood, with half-lives of 90 min (JMV4208) and 60 min (JMV3002), and disappeared from the blood 8h after administration. Fourteen days of treatment with the ghrelin antagonists (20 mg/kg twice a day) decreased food intake, body weight and adipose tissue mass in mice with diet-induced obesity (DIO). These results are likely attributable to an impact on food intake reduction and an attenuated expression of the lipogenesis-promoting enzymes (acetyl-CoA carboxylase 1 in subcutaneous fat and fatty acid synthase in subcutaneous and intraperitoneal fat). The decrease in fat mass negatively impacted circulating leptin levels. These data suggest that JMV4208 and JMV3002 could be useful therapeutic agents for the treatment of obesity.
3rd Department of Medicine 1st Faculty of Medicine Charles University Prague Prague Czech Republic
IBMM UMR 5274 CNRS Universités Montpellier 1 Montpellier 2 Faculté de Pharmacie Montpellier France
Institute of Chemical Technology Department of Analytical Chemistry Prague Czech Republic
Institute of Organic Chemistry and Biochemistry AS CR Prague Czech Republic
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