MULLER, Tania; DEMIZIEUX, Laurent; TROY FIORAMONTI, Stephanie; BUCH, Chloe; LEEMPUT, Julia; BELLOIR, Christine; DE BARROS, J.-P.P.; JOURDAN, Tony; PASSILLY DEGRACE, Patricia; FIORAMONTI, Xavier; LE, Bon, A.-M.; VERGÈS, B.; ROBERT, J.-M.; DEGRACE, P.

doi:10.3390/ijms23062923

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Article de revue

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International journal of molecular sciences. 2022-03-08, vol. 23, n° 6

Résumé en anglais

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. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.< Réduire

Mots clés en anglais

Endocannabinoid system

CB1R antagonist

Rimonabant

SWISSADME prediction

Drug discovery

Pharmacokinetics

Obesity

URI

https://oskar-bordeaux.fr/handle/20.500.12278/172232

DOI

http://dx.doi.org/10.3390/ijms23062923

Project ANR

Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer - ANR-11-LABX-0021

Unités de recherche

NutriNeuro (Laboratoire de Nutrition et Neurobiologie Intégrée) - UMR 1286

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Chemical Synthesis, Pharmacokinetic Properties and Biological Effects of JM-00266, a Putative Non-Brain Penetrant Cannabinoid Receptor 1 Inverse Agonist