Central Versus Peripheral Antagonism of Cannabinoid CB1 Receptor in Obesity: Effects of LH‐21, a Peripherally Acting Neutral Cannabinoid Receptor Antagonist, in Zucker Rats

Abstract

The endocannabinoid system as a new modulator of feeding and energy expenditureThe endogenous cannabinoid system is a lipid signalling system comprising arachidonic acid derivatives (N-acylethanolamides and 2-arachidonoyl glycerol and related compounds) that has recently been identified as a major homeostatic system in brain and peripheral tissues. The N-acylethanolamides anandamide and oleoylethanolamide (OEA) are lipid mediators that regulate feeding, lipid metabolism and energy balance. Both of them can show opposite effects to one another, however, and act through different mechanisms (1-5). While OEA is a peroxisome proliferator activated receptor a (PPARa) agonist (6) that decreases food intake and promotes lipid mobilisation and oxidation (4,7,8), anandamide is a cannabinoid CB 1 receptor agonist that promotes feeding and energy storage (2, 3, 9, 10). Anandamide and OEA are released in a coordinated way; following feeding ⁄ starvation cycles, anandamide stimulates food seeking whereas OEA induces satiety (2, 4). Because The endogenous cannabinoid system plays an important modulatory role in feeding behaviour and metabolism, acting at both central and peripheral levels. Chronic administration of cannabinoid CB 1 receptor antagonists has been found to be effective in experimental obesity. However, clinically available cannabinoid receptor antagonists are inverse agonists that can target CB 1 receptors located in both central circuits regulating appetite and motivation and in peripheral organs regulating metabolism and energy expenditure. This profile complicates understanding of cannabinoid CB 1 receptor blockade as a therapeutic strategy in obesity and metabolic disorders. This review aims to explore the relevance of both inverse agonism and peripheral cannabinoid receptor blockade on the beneficial actions of chronic cannabinoid receptor blockade, by comparing the actions of the reference antagonist ⁄ inverse agonist rimonabant and the newly designed drug LH-21. LH-21 is a triazol derivative and a neutral cannabinoid receptor antagonist; it has a poor penetration rate into the central nervous system. When given acutely it decreases food intake and enhances the anorectic actions of oleoylethanolamide, a feeding suppressant lipid that acts on peripheral sensory terminals in a similar way as rimonabant. Unlike rimonabant, chronic administration of LH-21 (3 mg ⁄ kg) reduces feeding but does not improve hypertriglyceridaemia or hypercholesterolaemia; nor does it reduce liver fat deposits in Zucker rats. These results suggest that the inverse agonism and ⁄ or the antagonism of central cannabinoid CB 1 receptors are necessary for the metabolic benefits of cannabinoid CB 1 receptor blockade, but not for the appetite reduction. Journal of Neuroendocrinology

Obesity and the Endocannabinoid System: Is There Still a Future for CB1 Antagonists in Obesity?

“…Additionally, this combinational therapy reduces the hepatic steatosis observed in obese rats, decreasing liver fat depots and improving liver function [133]. A similar effect has been observed with the combination of LH-21 and OEA [102].…”

“…LH-21 displays a different pharmacological profile in comparison with rimonabant [101,102]. Acute administration of this compound reduces food intake in fasted rats [101].…”

Peripherally acting CB1-receptor antagonist: the relative importance of central and peripheral CB1 receptors in adiposity control

“…8 SR141716A (N-(piperidin-1-yl)-5-4-chlorophenyl)-1-2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride) (code name for rimonabant, withdrawn from the markets since October 2008), a CB1-receptor antagonist and also classified as an inverse agonist, modulates food intake by acting on CB1 receptors located on capsaicin-sensitive sensory terminals. 9 Pavon et al 10,11 demonstrated that LH-21, a peripherally acting neutral CB-receptor antagonist, has antiobesity effects in vivo. Thereafter, Chen et al 12 suggested that LH-21 does not act on the CB1 receptor to inhibit food intake in mice.…”

Synthesis and pharmacological evaluation of new (E)- and (Z)-3-aryl-4-styryl-1H-pyrazoles as potential cannabinoid ligands

“…23 At present, different cannabinoid ligands have been identified, 24,25 which can be classified into different chemical families. [27][28][29][30] Among the different classes of synthetic compounds assuring CB 1 or CB 2 affinity and selectivity, the relevance of pyrazole derivatives has been consolidated by various studies and the pyrazole moiety is regarded as a versatile scaffold in the cannabinoid research field.…”

“…MS (10), 171 (100), 160 (7), 145 (5), 124 (4), 96 (2), 64 (13). HRMS-EI m/z for C 30 4; and 0.1% BSA). The homogenates were centrifuged at 3000 rpm for 10 min, and the supernatants were then recentrifuged at 18000 rpm for 10 min.…”