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Phenylpiperidine opioid antagonists that promote weight loss in rats have high affinity for the (enkephalin-sensitive) binding site

1993; Elsevier BV; Volume: 14; Issue: 1 Linguagem: Inglês

10.1016/0196-9781(93)90005-2

1873-5169

Richard B. Rothman, Heng Xu, George U. Char, Andrew Kim, Brian R. de Costa, Kenner C. Rice, Dennis M. Zimmerman,

Receptor Mechanisms and Signaling

Certain opioid antagonists of the phenylpiperidine series (PPAs), such as LY255582, seem uniquely efficacious at producing weight loss in lean and meal-fed obese Zucker rats. Comparison of the pharmacological and receptor binding profile of PPAs that promote marked weight loss with those that do not has failed to find any obvious differences between these two groups of narcotic antagonists, which might explain the differences in their biological activities. The potent stimulatory effect of dynorphin, and other κ agonists, on feeding behavior suggests that the antagonists that promote weight loss might have high affinity for κ receptors. The recent demonstration by several laboratories of κ receptor heterogeneity prompted us to test the hypothesis that the antagonists that promote weight loss might have high affinity for a subtype of κ binding sites. In the present study, therefore, we determined the Ki values of five PPAs, naloxone, and naltrexone at μ, δ, κ1, κ2a, and κ2b binding sites. The data indicate that antagonists having subnanomolar Ki values and high selectivity for the κ2b binding site (relative to the κ2a binding site) are efficacious at promoting weight loss.