Oral bioavailability of the novel cannabinoid CB1 antagonist AM6527: effects on food-reinforced behavior and comparisons with AM4113

Drugs that interfere with cannabinoid CB1 transmission suppress food-motivated behaviors, and may be clinically useful as appetite suppressants. Several CB1 receptor inverse agonists, such as rimonabant and AM251, as well as the CB1 receptor neutral antagonist, AM4113, have been assessed for their effects on food-motivated behavior. One important criterion for establishing if a drug may be useful clinically is the determination of its oral bioavailability. The present studies compared the effects of AM4113 and a novel CB1 antagonist, AM6527, on the suppression of food-reinforced behavior following intraperitoneal (IP) and oral administration. AM4113 and AM6527 both suppressed lever pressing after IP injections. The ED₅₀ for the effect on FR5 responding was 0.78 mg/kg for IP AM4113, and 0.5763 mg/kg for IP AM6527. AM6527 also was effective after oral administration (ED₅₀ = 1.49 mg/kg), however, AM 4113 was ineffective up to oral doses of 32.0 mg/kg. AM 4113 may be very useful as a research tool, but its lack of oral activity suggests that this drug might not be effective if orally administered in humans. In contrast, AM 6527 is an orally active CB1 antagonist, which may be useful for clinical research on the appetite suppressant effects of CB1 antagonists.