title: Potent inhibition of alcohol self-administration in alcohol-preferring rats by a κ-opioid receptor antagonist.
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.
authors.affiliation: Human BioMolecular Research Institute, San Diego, California (J.R.C.); and Behavioral Pharma, Inc., La Jolla, California (M.R.A.) jcashman@hbri.org.
authors.forename: John R
authors.initials: JR
authors.lastname: Cashman
authors.affiliation: Human BioMolecular Research Institute, San Diego, California (J.R.C.); and Behavioral Pharma, Inc., La Jolla, California (M.R.A.).
authors.forename: Marc R
authors.initials: MR
authors.lastname: Azar
mesh_terms: D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood; D003216:Conditioning, Operant / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D009019:Morphinans / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D009271:Naltrexone / Q000009:adverse effects / Q000031:analogs & derivatives*; D009292:Narcotic Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012646:Self Administration; D013854:Thioamides / Q000037:antagonists & inhibitors
chemical_list: D009019:Morphinans; D009292:Narcotic Antagonists; D013854:Thioamides; D000431:Ethanol; D009271:Naltrexone; C015539:thiobenzamide; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase