title: Triazole GHS-R1a antagonists JMV4208 and JMV3002 attenuate food intake, body weight, and adipose tissue mass in mice.
abstract: 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.
authors: Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic; Third Department of Medicine, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors: M
authors: M
authors: Holubová
authors: Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic.
authors: V
authors: V
authors: Nagelová
authors: Third Department of Medicine, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors: Z
authors: Z
authors: Lacinová
authors: Third Department of Medicine, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors: M
authors: M
authors: Haluzík
authors: Institute of Chemical Technology, Department of Analytical Chemistry, Prague, Czech Republic.
authors: D
authors: D
authors: Sýkora
authors: IBMM UMR 5274, CNRS - Universités Montpellier 1- Montpellier 2, Faculté de Pharmacie, Montpellier, France.
authors: A
authors: A
authors: Moulin
authors: IBMM UMR 5274, CNRS - Universités Montpellier 1- Montpellier 2, Faculté de Pharmacie, Montpellier, France.
authors: A L
authors: AL
authors: Blayo
authors: IBMM UMR 5274, CNRS - Universités Montpellier 1- Montpellier 2, Faculté de Pharmacie, Montpellier, France.
authors: J A
authors: JA
authors: Fehrentz
authors: IBMM UMR 5274, CNRS - Universités Montpellier 1- Montpellier 2, Faculté de Pharmacie, Montpellier, France.
authors: J
authors: J
authors: Martinez
authors: Department of Normal, Pathological and Clinical Physiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
authors: A
authors: A
authors: Stofkova
authors: Department of Normal, Pathological and Clinical Physiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
authors: J
authors: J
authors: Jurčovičová
authors: Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic.
authors: B
authors: B
authors: Zelezná
authors: Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic. Electronic address: maletin@uochb.cas.cz.
authors: L
authors: L
authors: Maletínská
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects*; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010848:Picolinic Acids / Q000737:chemistry / Q000494:pharmacology*; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000598418:JMV3002; C000598419:JMV4208; D010848:Picolinic Acids; D054440:Receptors, Ghrelin; D014230:Triazoles
keywords: Diet-induced obesity; Food intake; GHS-R1a antagonists; JMV3002; JMV4208; Male C57BL/6 mice