A novel nociceptin receptor antagonist inhibits feeding behavior in rodents (656.1)

Background: Nociceptin is a 17 amino acid peptide that produces physiological effects through activation of the ORL1 (NOP) receptor. We have identified a novel NOP antagonist (Cpd 1) and found it to have high binding affinity (Ki = 0.11 nM), antagonist potency (Kb = 0.17 nM) and selectivity for NOP. Cpd 1 is orally active, CNS penetrant and potently occupies NOP receptors in vivo. Herein, the effects of Cpd 1 on feeding behavior and metabolism were studied. Methods: Male, lean and dietary‐induced obese (DIO) rats, DIO mice and NOP knockout (KO) mice were used in feeding and indirect calorimetry studies. Results: Consistent with the literature, Cpd 1 reduced food intake in rodents. In lean rats, Cpd 1 inhibited consumption of a highly palatable (high fat/sucrose) diet, reducing the calorie intake to control chow levels. In DIO rats, Cpd 1 inhibited feeding induced by a mild caloric restriction. In DIO mice, Cpd 1 decreased 24 hr free access food intake and decreased the respiratory quotient indicating that metabolism was driven by fat utilization. Fasting‐induced feeding was inhibited by Cpd 1 in 129S6 mice, an effect that was absent in NOP KO mice. Moreover, under vehicle conditions fasting‐induced feeding was reduced in NOP KO mice. Conclusions: These data support that Cpd 1 potently inhibits feeding behavior and stimulates fat utilization in rodents. Moreover, the hypophagic effect of Cpd 1 is dependent on NOP receptors. Grant Funding Source : Eli Lilly and Company