PT  - JOURNAL ARTICLE
AU  - Cashman, John R.
AU  - Azar, Marc R.
TI  - Potent Inhibition of Alcohol Self-Administration in Alcohol-Preferring Rats by a <em>κ</em>-Opioid Receptor Antagonist
AID  - 10.1124/jpet.114.214262
DP  - 2014 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 171--180
VI  - 350
IP  - 1
4099  - http://jpet.aspetjournals.org/content/350/1/171.short
4100  - http://jpet.aspetjournals.org/content/350/1/171.full
SO  - J Pharmacol Exp Ther2014 Jul 01; 350
AB  - 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.