Behavioral effects of the cannabinoid CB1 receptor negative modulator ORG27569 in rats (838.2)

Abstract

Orthosteric cannabinoid CB1 receptor antagonists are effective for treating obesity but also have serious side effects (e.g., depression) which limit their clinical utility. Negative allosteric modulators might possess different therapeutic and side effect profiles. This study examined the behavioral effects of a CB1 receptor negative allosteric modulator ORG27569 in rats. CB1 receptor agonists CP55940 (0.1‐1 mg/kg) and anandamide (3.2‐32 mg/kg) dose‐dependently decreased the body temperature in rats. ORG27569 alone had no effect on the body temperature but markedly antagonized CP55940‐ and anandamide‐induced hypothermic effects. CP55940 (0.032‐1 mg/kg) produced marked cataleptic effect. Although the CB1 receptor orthosteric antagonist rimonabant markedly antagonized the cataleptic effect of CP55940, ORG27569 did not alter such an effect. Rimonabant dose‐dependently increased the frequency of grooming and scratching behaviors in rats. ORG27569 alone did not increase the frequency of these observational behaviors and did not alter the potency of rimonabant in this assay. These data suggest that ORG27569 has a different antagonism profile from the orthosteric CB1 receptor antagonist rimonabant in vivo. A better understanding of the antagonism profile of ORG27569 is warranted which may eventually lead to useful therapeutic actions via biased CB1 receptor blockade.(DA034806 and DA033426)