The effect of the opioid antagonist LY255582 on body weight of the obese Zucker rat.

The effects of the phenylpiperidine opioid antagonist, LY255582, on food consumption, water consumption and body weight gain of the meal-fed obese Zucker rat have been determined. A single subcutaneous dose of LY255582 (0.31 mg/kg) decreased food and water consumption of the meal-fed obese rat. LY255582 was effective as an appetite suppressant at lower doses than ephedrine, amphetamine, fenfluramine, naltrexone and nalmefene. Comparison of the relative in vivo biological activity with in vitro receptor binding assays of LY255582 and its stereoisomers shows that the order of the affinity of the mu and kappa opioid receptors correlates well with biological activity. LY255582 is the most biologically effective and has the highest affinity for both receptors. LY255582 administered chronically to meal-fed obese Zucker rats for 68 days at a subcutaneous dose of 0.31 mg/kg significantly reduced food and water consumption and decreased body weight gain during the entire treatment period. There was no development of tolerance to the biological effects of LY255582.