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.
Highlights
The endocannabinoid system (ECS) is comprised of cannabinoid receptors, their endogenous ligands and proteins responsible for their synthesis and degradation
Accumulating evidence indicates that the inactivation of peripheral cannabinoid 1 receptors (CB1R) represents a promising therapeutic strategy to control obesity and related metabolic disorders
We describe a new compound, JM-00266, designed from the specific CB1R inverse agonist Rimonabant template incorporating polar functionality
Summary
The endocannabinoid system (ECS) is comprised of cannabinoid receptors, their endogenous ligands (endocannabinoids) and proteins responsible for their synthesis and degradation. Cannabinoid-1 receptor (CB1R) is highly expressed in the brain where it plays key roles in the control of nociception, appetite, motor activity, mood, and memory [1]. CB1R is present in peripheral organs involved in the control of energy metabolism, including the liver, intestine, pancreas, muscle and adipose tissue [2]. This receptor emerged as a critical regulator of lipid metabolism, gastrointestinal motility, or cardiovascular function [3]. The identification of a role for ECS in the regulation of food intake and energy metabolism suggested therapeutic strategies aimed at blocking
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