A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents

Abstract

BACKGROUND AND PURPOSE Cannabinoid CB1 receptor antagonists reduce food intake and body weight, but clinical use in humans is limited by effects on the CNS. We have evaluated a novel cannabinoid antagonist (AM6545) designed to have limited CNS penetration, to see if it would inhibit food intake in rodents, without aversive effects. EXPERIMENTAL APPROACH Cannabinoid receptor binding studies, cAMP assays, brain penetration studies and gastrointestinal motility studies were carried out to assess the activity profile of AM6545. The potential for AM6545 to induce malaise in rats and the actions of AM6545 on food intake and body weight were also investigated. KEY RESULTS AM6545 binds to CB1 receptors with a Ki of 1.7 nM and CB2 receptors with a Ki of 523 nM. AM6545 is a neutral antagonist, having no effect on cAMP levels in transfected cells and was less centrally penetrant than AM4113, a comparable CB1 receptor antagonist. AM6545 reversed the effects of WIN55212‐2 in an assay of colonic motility. In contrast to AM251, AM6545 did not produce conditioned gaping or conditioned taste avoidance in rats. In rats and mice, AM6545 dose‐dependently reduced food intake and induced a sustained reduction in body weight. The effect on food intake was maintained in rats with a complete subdiaphragmatic vagotomy. AM6545 inhibited food intake in CB1 receptor gene‐deficient mice, but not in CB1/CB2 receptor double knockout mice. CONCLUSIONS AND IMPLICATIONS Peripherally active, cannabinoid receptor antagonists with limited brain penetration may be useful agents for the treatment of obesity and its complications.

MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future

“…Some of these drugs, such as the peripherally restricted CB 1 R inverse agonist JD5037 and the CB 1 R antagonist AM6545 have been shown to reduce obesity, reverse leptin resistance and improve hepatic steatosis, dyslipidemia and insulin resistance in genetically and diet-induced obese mice (63,119,120). These are quite important observations, because they imply that the blockade of CNS CB 1 Rs is not required for the treatment of metabolic disease.…”

Cannabinoids and their medicinal potential

“…This alongside also led to the termination of development of other CB 1 receptor blockers like taranabant and otanabant. 17,18 Still the interest in the potential of CB 1 antagonists called the peripherally restricted CB 1 receptor antagonists is retained and several such compounds are being synthesized and developed. These compounds will attain lower brain concentrations and will be free of the aversive side effects seen with rimonabant.…”

“…These compounds will attain lower brain concentrations and will be free of the aversive side effects seen with rimonabant. [17][18][19] A novel peripherally active cannabinoid receptor antagonist, AM6545, which is more selective for CB 1 than CB 2 was tested in rodents to evaluate its effect on food intake and body weight. This agent showed limited brain permeability and dose dependently reduced food intake and inhibited body weight gain in rodents.…”

“…This agent showed limited brain permeability and dose dependently reduced food intake and inhibited body weight gain in rodents. 17 Hence CB 1 receptor antagonists designed to have limited brain permeability hold a promising future in weight management.…”

“…Therefore selectively targeting CB 1 receptors with agents lacking brain penetrance may prove to be an effective treatment option in such patients. 67,68 The role of CB 2 receptors on adipose tissue inflammation was also evaluated. It was seen that treatment with CB 2 selective agonist in obese mouse model, led to increase in insulin resistance and liver steatogenesis associated with obesity.…”