Chemical Synthesis, Pharmacokinetic Properties and Biological Effects of JM-00266, a Putative Non-Brain Penetrant Cannabinoid Receptor 1 Inverse Agonist.
Tania MullerLaurent DemizieuxStéphanie Troy-FioramontiChloé BuchJulia LeemputChristine BelloirJean-Paul Pais de BarrosTony JourdanPatricia Passilly-DegraceXavier FioramontiAnne-Marie Le BonBruno VergèsJean-Michel RobertPascal DegracePublished in: International journal of molecular sciences (2022)
Targeting cannabinoid 1 receptors (CB1R) with peripherally restricted antagonists (or inverse agonists) shows promise to improve metabolic disorders associated with obesity. In this context, we designed and synthetized JM-00266, a new CB1R blocker with limited blood-brain barrier (BBB) permeability. Pharmacokinetics were tested with SwissADME and in vivo in rodents after oral and intraperitoneal administration of JM-00266 in comparison with Rimonabant. In silico predictions indicated JM-00266 is a non-brain penetrant compound and this was confirmed by brain/plasma ratios and brain uptake index values. JM-00266 had no impact on food intake, anxiety-related behavior and body temperature suggesting an absence of central activity. cAMP assays performed in CB1R-transfected HEK293T/17 cells showed that the drug exhibited inverse agonist activity on CB1R. In addition, JM-00266 counteracted anandamide-induced gastroparesis indicating substantial peripheral activity. Acute administration of JM-00266 also improved glucose tolerance and insulin sensitivity in wild-type mice, but not in CB1R -/- mice. Furthermore, the accumulation of JM-00266 in adipose tissue was associated with an increase in lipolysis. In conclusion, JM-00266 or derivatives can be predicted as a new candidate for modulating peripheral endocannabinoid activity and improving obesity-related metabolic disorders.
Keyphrases
- blood brain barrier
- adipose tissue
- high fat diet induced
- cerebral ischemia
- resting state
- wild type
- insulin resistance
- white matter
- metabolic syndrome
- type diabetes
- drug induced
- weight loss
- functional connectivity
- weight gain
- physical activity
- signaling pathway
- drug delivery
- emergency department
- high throughput
- endothelial cells
- respiratory failure
- molecular docking
- brain injury
- hepatitis b virus
- subarachnoid hemorrhage
- high glucose
- deep learning
- sleep quality