The cannabinoid 1 receptor (CB1R) is one of the most abundant G protein-coupled receptors (GPCRs) in the central nervous system, with key roles during neurotransmitter release and synaptic plasticity[3]. JD5037 is a novel peripherally restricted CB1 receptor (CB1R) inverse agonist being developed for the treatment of visceral obesity and its metabolic complication, including nonalcoholic fatty liver disease and dyslipidemia. JD5037 was administered by oral gavage at 10, 40, and 150 mg/kg/day dose levels for up to 34 days to Sprague Dawley rats, and higher incidences of stereotypic behaviors were observed in 10 mg/kg females and 40 mg/kg males, and slower responses for reflex and sensory tests were observed only in males at 10 and 40 mg/kg during neurobehavioral testing. Results showed highest dose resulted in lower AUCs indicative of non-linear kinetics[4]. JD5037 treatment of alcohol-drinking mice inhibits the formation of biologically active octanoyl-ghrelin without affecting its inactive precursor desacyl-ghrelin. In ghrelin-producing stomach cells, JD5037 reduced the level of the substrate octanoyl-carnitine generated from palmitoyl-carnitine by increasing fatty acid β-oxidation[5].
JD-5037 细胞实验
Cell Line
Concentration
Treated Time
Description
References
3T3 L1 adipocytes
100 nM
24 h
JD5037 reversed CB1R agonist-induced increases in leptin secretion
Cell Metab. 2012 Aug 8;16(2):167-79.
MGN3-1 cells
100 nM
6 h
To study the effect of JD5037 on fatty acid uptake and processing in MGN3-1 cells, results showed that JD5037 significantly increased the uptake of [2H31]palmitic acid and the generated labeled acyl-carnitine species.
Cell Metab. 2019 Jun 4;29(6):1320-1333.e8.
HepG2 cells
10 μM
1 hour
To study the effect of JD-5037 on insulin signaling, results showed that JD-5037 could block the inhibition of insulin-induced akt phosphorylation.
Hepatology. 2014 Jan;59(1):143-53.
Mouse primary hepatocytes
10 μM
To study the effect of JD-5037 on ceramide synthesis, results showed that JD-5037 could block ceramide synthesis.
Hepatology. 2014 Jan;59(1):143-53.
HepG2 cells
100 nM
overnight
JD5037 reversed the inhibitory effects of ACEA on insulin-induced Akt phosphorylation, indicating that the Sirt1/mTORC2/Rictor signaling pathway plays a key role in the reversal of insulin signaling inhibition by CB1R antagonists.
Hepatology. 2019 Apr;69(4):1535-1548.
primary mouse hepatocytes
100 nM
25 h
JD5037 reversed the inhibitory effects of ACEA on Sirt1 and Rictor expression, indicating that the CB1R antagonist reversed the inhibition of insulin signaling via the Sirt1/mTORC2 pathway.
Hepatology. 2019 Apr;69(4):1535-1548.
HepG2 cells
1–5 μM
1 hour
To analyze the mechanism of CB1R-dependent FOXM1 expression, results showed that AEA significantly induced FOXM1 expression, and this induction was blocked by pertussis toxin.
Hepatology. 2015 May;61(5):1615-26.
Bone marrow-derived macrophages (BMDMs)
1 µM
24 h
To study the effect of CB1 agonist ACEA on BMDM proliferation, results showed that ACEA increased BMDM proliferation.
Cardiovasc Res. 2024 Oct 14;120(12):1411-1426.
Bone marrow-derived macrophages (BMDMs)
10 µM
24 h
To study the effect of CB1 antagonist AM281 on BMDM proliferation, results showed that AM281 inhibited BMDM proliferation.
Cardiovasc Res. 2024 Oct 14;120(12):1411-1426.
Human islet cells
10 nM
6 days
To investigate the effect of JD-5037 on insulitis, results showed that JD-5037 significantly reduced cytokine-induced accumulation and immune cell infiltration into islets.
Diabetologia. 2024 Sep;67(9):1877-1896.
JD-5037 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
C57BL/6J mice
Oral
3 mg/kg
Once daily for 5 days
To study the effect of JD5037 on alcohol intake and preference in mice, results showed that JD5037 significantly reduced ethanol intake and preference.
Cell Metab. 2019 Jun 4;29(6):1320-1333.e8.
Mice
Diet-induced obese mice
Oral
3 mg/kg
Daily for 28 days
JD5037 reduced food intake,, and adiposity, and reversed leptin resistance
Cell Metab. 2012 Aug 8;16(2):167-79.
Mice
High-fat diet-induced obese mice
Intraperitoneal injection
3 mg/kg
Once daily for 28 days
To study the effect of JD-5037 on, steatosis, glucose tolerance, and insulin sensitivity in obese mice, results showed that JD-5037 could reduce, improve steatosis, enhance glucose tolerance, and increase insulin sensitivity.
Hepatology. 2014 Jan;59(1):143-53.
Mice
High-fat diet-induced obese mice
Oral gavage
3 mg/kg
Daily for 2 or 4 weeks
JD5037 treatment reversed the HFD-induced suppression of Sirt1/mTORC2 signaling, improved insulin sensitivity and glycemic control, and increased fatty acid oxidation and energy expenditure.
Hepatology. 2019 Apr;69(4):1535-1548.
Mice
DEN-induced liver cancer model
Oral gavage
3 mg/kg
Once daily for 8 weeks
To evaluate the inhibitory effect of JD5037 on DEN-induced liver cancer, results showed that JD5037 significantly reduced tumor volume.
Hepatology. 2015 May;61(5):1615-26.
Mice
Atherosclerosis model
Intraperitoneal injection
3 mg/kg
Daily for 4 weeks
To study the effect of peripheral CB1 antagonist JD5037 on atherosclerosis plaque progression, results showed that JD5037 inhibited plaque progression and reduced macrophage accumulation and proliferation in male mice.
Cardiovasc Res. 2024 Oct 14;120(12):1411-1426.
Mice
NOD mice
Intraperitoneal injection
3 mg/kg
Once daily for 1 week
To investigate the effect of JD-5037 on insulitis, results showed that JD-5037 significantly prevented immune cell infiltration into the islets.
Diabetologia. 2024 Sep;67(9):1877-1896.
Mice
Magel2-null mice
Intraperitoneal injection
3 mg/kg
Once daily for 28 days
JD5037, through peripheral CB1 receptor antagonism, reversed the obese phenotype in Magel2-null mice, reduced hyperphagia, and improved metabolic parameters.
Mol Metab. 2016 Oct 22;5(12):1187-1199
Mice
CCl4-induced fibrotic liver model
Oral
3 mg/kg
Once daily for 8 weeks
To investigate the inhibitory effect of JD-5037 on liver fibrosis, results showed that JD-5037 attenuated liver fibrosis by blocking the CB1 receptor/β-arrestin1/Akt signaling pathway.
Br J Pharmacol. 2020 Jun;177(12):2830-2847
Mice
Mdr2−/− mice
Oral gavage
3 mg/kg
Every other day for 4 weeks
JD5037 significantly exacerbated liver injury in Mdr2?/? mice, evidenced by elevated serum ALT and ALP levels and exacerbated liver histology. JD5037-treated Mdr2?/? mice exhibited significantly heightened serum bile acid levels. JD5037 treatment intensified liver fibrosis, increased fibrogenic gene expression, stimulated ductular reaction, and upregulated hepatic proinflammatory cytokines.
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