3,4-DIMETHYL-4-(3-HYDROXYPHENYL)PIPERIDINES - OPIOID ANTAGONISTS WITHPOTENT ANORECTANT ACTIVITY

A series of R,4R*)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists with varying substituents on the nitrogen were evaluated f or their effect on food consumption in obese Zucker rats. Opioid affin ity (mu, kappa, and delta for selected compounds) and opioid antagonis t activity (mu and kappa) were characterized and compared to effects o n food consumption. No compounds with high selectivity for either mu o r kappa receptors were discovered. However, compounds in the series ha d exceptional potency as opioid antagonists and in reducing food consu mption in the obese Zucker rat. In contrast, a few compounds with high potency as opioid antagonists had much weaker potency for inhibiting food consumption. -4-(3-hydroxyphenyl)piperidine(11,LY255582)emerged a s having the best activity profile, both in reducing food consumption and as an opioid antagonist. Compound 11 is a highly potent mu, kappa- , and delta-opioid antagonist with possible clinical utility as an app etite suppressant for weight loss.