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- Title
Chemical Synthesis, Pharmacokinetic Properties and Biological Effects of JM-00266, a Putative Non-Brain Penetrant Cannabinoid Receptor 1 Inverse Agonist.
- Authors
Muller, Tania; Demizieux, Laurent; Troy-Fioramonti, Stéphanie; Buch, Chloé; Leemput, Julia; Belloir, Christine; Pais de Barros, Jean-Paul; Jourdan, Tony; Passilly-Degrace, Patricia; Fioramonti, Xavier; Le Bon, Anne-Marie; Vergès, Bruno; Robert, Jean-Michel; Degrace, Pascal
- Abstract
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.
- Subjects
CHEMICAL synthesis; CANNABINOID receptors; PHARMACOKINETICS; METABOLIC disorders; BODY temperature; INSULIN sensitivity; BLOOD-brain barrier; ADIPOSE tissues
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 6, p2923
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms23062923