Abstract

A substituted aryl amide derivative of 6-naltrexamine—17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-trimethylfluoro)benzamido]morphinan-hydrochloride—(compound 5), previously shown to be a potent κ-opioid receptor antagonist, was used to characterize the physicochemical properties and efficacy to decrease alcohol self-administration in alcohol-preferring rats (P-rats) and binge-like P-rats. Previous studies showed that compounds closely related to compound 5 possessed favorable properties regarding penetration of the blood-brain barrier. Pharmacokinetic studies showed that compound 5 had acceptable bioavailability. In contrast to other κ-receptor antagonists, in particular norbinaltorphimine, compound 5 showed favorable drug-like properties. Based on these findings, further studies were done. Safety studies showed that compound 5 was not hepatotoxic at doses 200-fold greater than an efficacious dose. The effects of compound 5 or naltrexone on the hepatotoxicity of thiobenzamide were investigated. In contrast to naltrexone, which exacerbated thiobenzamide-mediated hepatotoxicity, compound 5 was observed to be hepatoprotective. Based on the physicochemical properties of compound 5, the compound was examined in rat animal models of alcohol self-administration. The inhibition of ethanol self-administration by compound 5 in alcohol-dependent and alcohol-nondependent P-rats trained to self-administer a 10% (w/v) ethanol solution, using operant techniques, showed very potent efficacy (i.e., estimated ED₅₀ values of 4–5 μg/kg). In a binge-like P-rat animal model, inhibition of alcohol self-administration by compound 5 had an estimated ED₅₀ value of 8 μg/kg. The results suggest that compound 5 is a potent drug-like κ-opioid receptor antagonist of utility in alcohol cessation medications development.