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Chemical Synthesis, Pharmacokinetic Properties and Biological Effects of JM-00266, a Putative Non-Brain Penetrant Cannabinoid Receptor 1 Inverse Agonist
| dc.rights.license | open | en_US |
| dc.contributor.author | MULLER, Tania | |
| dc.contributor.author | DEMIZIEUX, Laurent | |
| dc.contributor.author | TROY FIORAMONTI, Stephanie | |
| dc.contributor.author | BUCH, Chloe | |
| dc.contributor.author | LEEMPUT, Julia | |
| hal.structure.identifier | Centre des Sciences du Goût et de l'Alimentation [Dijon] [CSGA] | |
| dc.contributor.author | BELLOIR, Christine | |
| dc.contributor.author | DE BARROS, J.-P.P. | |
| dc.contributor.author | JOURDAN, Tony | |
| dc.contributor.author | PASSILLY DEGRACE, Patricia | |
| hal.structure.identifier | Nutrition et Neurobiologie intégrée [NutriNeuro] | |
| hal.structure.identifier | Centre des Sciences du Goût et de l'Alimentation [Dijon] [CSGA] | |
| dc.contributor.author | FIORAMONTI, Xavier | |
| dc.contributor.author | LE, Bon, A.-M. | |
| dc.contributor.author | VERGÈS, B. | |
| dc.contributor.author | ROBERT, J.-M. | |
| dc.contributor.author | DEGRACE, P. | |
| dc.date.accessioned | 2023-03-09T11:15:20Z | |
| dc.date.available | 2023-03-09T11:15:20Z | |
| dc.date.issued | 2022-03-08 | |
| dc.identifier.issn | 1661-6596 | en_US |
| dc.identifier.uri | https://oskar-bordeaux.fr/handle/20.500.12278/172232 | |
| dc.description.abstractEn | 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. | |
| dc.description.sponsorship | Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer - ANR-11-LABX-0021 | en_US |
| dc.language.iso | EN | en_US |
| dc.rights | Attribution 3.0 United States | * |
| dc.rights.uri | http://creativecommons.org/licenses/by/3.0/us/ | * |
| dc.subject.en | Endocannabinoid system | |
| dc.subject.en | CB1R antagonist | |
| dc.subject.en | Rimonabant | |
| dc.subject.en | SWISSADME prediction | |
| dc.subject.en | Drug discovery | |
| dc.subject.en | Pharmacokinetics | |
| dc.subject.en | Obesity | |
| dc.title.en | Chemical Synthesis, Pharmacokinetic Properties and Biological Effects of JM-00266, a Putative Non-Brain Penetrant Cannabinoid Receptor 1 Inverse Agonist | |
| dc.type | Article de revue | en_US |
| dc.identifier.doi | 10.3390/ijms23062923 | en_US |
| dc.subject.hal | Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC] | en_US |
| dc.identifier.pubmed | 35328343 | en_US |
| bordeaux.journal | International journal of molecular sciences | en_US |
| bordeaux.volume | 23 | en_US |
| bordeaux.hal.laboratories | NutriNeurO (Laboratoire de Nutrition et Neurobiologie Intégrée) - UMR 1286 | en_US |
| bordeaux.issue | 6 | en_US |
| bordeaux.institution | Université de Bordeaux | en_US |
| bordeaux.institution | INRAE | en_US |
| bordeaux.peerReviewed | oui | en_US |
| bordeaux.inpress | non | en_US |
| bordeaux.identifier.funderID | Société Francophone du Diabète | en_US |
| hal.export | false | |
| dc.rights.cc | CC BY | en_US |
| bordeaux.COinS | ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=International%20journal%20of%20molecular%20sciences&rft.date=2022-03-08&rft.volume=23&rft.issue=6&rft.eissn=1661-6596&rft.issn=1661-6596&rft.au=MULLER,%20Tania&DEMIZIEUX,%20Laurent&TROY%20FIORAMONTI,%20Stephanie&BUCH,%20Chloe&LEEMPUT,%20Julia&rft.genre=article |
