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

BACKGROUND AND PURPOSE: Cannabinoid CB(1) 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 CB(1) receptors with a K(i) of 1.7 nM and CB(2) receptors with a K(i) 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 CB(1) 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 CB(1) receptor gene-deficient mice, but not in CB(1)/CB(2) 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.

Inverse agonism of cannabinoid CB1 receptors potentiates LiCl-induced nausea in the conditioned gaping model in rats.

BACKGROUND AND PURPOSE: Cannabinoid CB(1) receptor antagonists/inverse agonists, potentiate toxin-induced nausea and vomiting in animal models. Here, we sought to determine if this potentiated nausea was mediated by inverse agonism or neutral antagonism of the CB(1) receptor, and if the potentiated nausea would be produced by intracerebroventricular (icv) administration of an inverse agonist. EXPERIMENTAL APPROACH: The conditioned gaping model of nausea in rats was used to compare the CB(1) receptor antagonist/inverse agonist, AM251, and the CB(1) receptor neutral antagonists, AM6527 (centrally and peripherally active) and AM6545 (peripherally active), in potentiating conditioned gaping produced by lithium chloride (LiCl) solution. The effect of icv (lateral ventricle and 4th ventricle) administration of AM251 on LiCl-induced gaping in this model was also evaluated. KEY RESULTS: At a dose that did not produce conditioned gaping on its own, systemically administered AM251 (1.25 mg.kg(-1)) potentiated LiCl-induced conditioned gaping and reduced sucrose palatability; however, even doses as high as 8 mg.kg(-1) of AM6545 and AM6527 neither potentiated LiCl-induced conditioned gaping nor reduced sucrose palatability. Infusions of AM251 into the lateral ventricles (1.25, 12.5 and 125 microg) or the 4th ventricle (2.5, 12.5 and 125 microg) did not potentiate LiCl-induced conditioned gaping reactions, but all doses attenuated saccharin palatability during the subsequent test. CONCLUSIONS AND IMPLICATIONS: Inverse agonism, but not neutral antagonism, of CB(1) receptors potentiated toxin-induced nausea. This effect may be peripherally mediated or may be mediated centrally by action on CB(1) receptors, located distal to the cerebral ventricles.