Abstract
A substituted aryl amide derivative of 6-naltrexamine, compound 5, previously shown to be a potent kappa 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 5 possessed good blood-brain barrier penetrating properties. Pharmacokinetic studies showed that 5 had acceptable bioavailability. In contrast to other kappa receptor antagonists (i.e., nor-BNI) compound 5 showed favorable drug-like properties and further studies were done. Safety studies showed that 5 was not hepatotoxic at doses 200-fold greater than an efficacious dose. The effect of 5 or naltrexone on the hepatotoxicity of thiobenzamide was investigated. In contrast to naltrexone that exacerbated thiobenzamide-mediated hepatotoxicity, 5 was observed to be hepatoprotective. Based on the physicochemical properties of 5, the compound was examined in rat animal models of alcohol self-administration. The inhibition of ethanol self-administration by 5 in alcohol-dependent or alcohol-nondependent P-rats trained to self-administer a 10 % (w/v) ethanol solution, utilizing operant techniques showed very potent efficacy (i.e., estimated ED50 value 4-5 μg/kg). In a binge-like P-rat animal model, inhibition of alcohol self-administration by 5 had an estimated ED50 value of 8 μg/kg. The results suggest that 5 is a potent drug-like kappa opioid receptor antagonist of utility in alcohol cessation medications development.
- The American Society for Pharmacology and Experimental Therapeutics