Comparative Behavioral Studies of Rimonabant and a Peripherally Restricted CB1 Receptor Antagonist

Abstract

In recent years, cannabinoid subtype 1 receptor (CB1R) antagonists have been developed to treat obesity and metabolic syndrome. Unfortunately, rimonabant (SR141716A) the first marketed drug produced CNS‐related adverse effects including depression and suicidal ideation and was withdrawn from the market. Recent data suggest that blockade of peripheral CB1R receptors can mitigate symptoms associated with metabolic syndrome independent of CNS effects. Therefore, CNS‐sparing CB1R antagonists that have limited transport across the blood‐brain‐barrier are under development. We have developed several potent, selective and drug‐like small molecule inverse agonists of CB1R with vastly reduced brain exposure (e.g. RTI‐1092915). As part of an integrated drug discovery program it was deemed prudent to evaluate lead compounds for evidence of possible neuropsychiatric side effects.First, a behavioral battery was performed in rats to assess the effects of rimonabant after acute and chronic dosing regimens. Rimonabant (vehicle, 3, 10 mg/kg) was administered i.p. 30 minutes prior to the simultaneous assessment of locomotor activity, grooming, feeding, and defecation. Rimonabant significantly decreased food consumption, decreased measures of locomotor activity, increased scratching and wet‐dog shakes, and increased defecation. Subsequently, animals were dosed daily but were always tested in a drug‐free state, as not to test the acute effects of the drug on top of the background of chronic dosing. The highest dose of rimonabant tested significantly decreased marble burying behavior, presumably anxiolysis, while there were trends for anxiogenic effects in the light‐dark box. In an attempt to clarify these results, behavioral tests including forced swim test and preference in two‐bottle choice for sucrose were performed, however there was no effect of treatment. Chronic treatment with rimonabant also significantly attenuated weight gain in these animals despite having ad libitum food.A similar battery of behaviors was performed to directly compare rimonabant (10 mg/kg) to RTI‐ 1092915 (3 mg/kg; a dose previously shown to reduce alcoholic steatosis). There were no significant effects with RTI‐1092915 while rimonabant again acutely decreased food intake, weight gain and locomotor activity. The chronic dosing of rimonabant, but not RTI‐1092915, significantly decreased time spent near an intruder animal in a social interaction paradigm.Our preliminary data suggests that certain behaviors, either after acute or chronic dosing, could be used to distinguish peripherally restricted and CNS penetrant CB1R antagonists. Specifically, social interaction could be used to assess the negative impact of chronic treatment with centrally‐acting CB1R antagonists. Finally, RTI‐1092915 shows no or mitigated negative effects in the behaviors tested. Therefore, RTI‐1092915 may be a lead candidate to treat metabolic syndrome and liver diseases through inhibition of peripheral CB1R receptors.Support or Funding InformationNIH DK100414, AA023256This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.