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Research ArticleBehavioral Pharmacology

Potent Inhibition of Alcohol Self-Administration in Alcohol-Preferring Rats by a κ-Opioid Receptor Antagonist

John R. Cashman and Marc R. Azar
Journal of Pharmacology and Experimental Therapeutics July 2014, 350 (1) 171-180; DOI: https://doi.org/10.1124/jpet.114.214262
John R. Cashman
Human BioMolecular Research Institute, San Diego, California (J.R.C.); and Behavioral Pharma, Inc., La Jolla, California (M.R.A.)
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Marc R. Azar
Human BioMolecular Research Institute, San Diego, California (J.R.C.); and Behavioral Pharma, Inc., La Jolla, California (M.R.A.)
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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.

Footnotes

    • Received February 25, 2014.
    • Accepted May 8, 2014.
  • This work was financially supported by a grant from the National Institutes of Health [Grant AA016029] (to M.A.).

  • dx.doi.org/10.1124/jpet.114.214262.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 350 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 350, Issue 1
1 Jul 2014
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Research ArticleBehavioral Pharmacology

Potent Alcohol Cessation Agents

John R. Cashman and Marc R. Azar
Journal of Pharmacology and Experimental Therapeutics July 1, 2014, 350 (1) 171-180; DOI: https://doi.org/10.1124/jpet.114.214262

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Research ArticleBehavioral Pharmacology

Potent Alcohol Cessation Agents

John R. Cashman and Marc R. Azar
Journal of Pharmacology and Experimental Therapeutics July 1, 2014, 350 (1) 171-180; DOI: https://doi.org/10.1124/jpet.114.214262
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