Chemical Synthesis, Pharmacokinetic Properties and Biological Effects of JM-00266, a Putative Non-Brain Penetrant Cannabinoid Receptor 1 Inverse Agonist.
CB1R antagonist
Rimonabant
SWISSADME prediction
drug discovery
endocannabinoid system
obesity
pharmacokinetics
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
08 Mar 2022
08 Mar 2022
Historique:
received:
26
01
2022
revised:
28
02
2022
accepted:
01
03
2022
entrez:
25
3
2022
pubmed:
26
3
2022
medline:
9
4
2022
Statut:
epublish
Résumé
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
Identifiants
pubmed: 35328343
pii: ijms23062923
doi: 10.3390/ijms23062923
pmc: PMC8949893
pii:
doi:
Substances chimiques
Cannabinoid Receptor Antagonists
0
Receptor, Cannabinoid, CB1
0
Receptors, Cannabinoid
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Société Francophone du Diabète
ID : paf/cc 14-005
Organisme : Agence Nationale de la Recherche
ID : ANR-11-LABX-0021
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