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Cashman J.R.,Human BioMolecular Research Institute | Azar M.R.,Behavioral Pharma Inc.
Journal of Pharmacology and Experimental Therapeutics

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. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics. Source

Cashman J.R.,Human BioMolecular Research Institute | Okolotowicz K.,Human BioMolecular Research Institute | Cerny M.,Human BioMolecular Research Institute | Johnson R.,Veterans Administrative Hospital | And 2 more authors.

Rationale: Certain compounds that nonselectively inhibit a prominent human nicotine-metabolizing enzyme (i.e., human cytochrome P-450 2A6, hCYP 2A6) showed inhibition of smoking in humans. However, a comprehensive examination of hCYP 2A6 inhibitors to decrease nicotine self-administration in rats has not been reported. Objectives: We tested substituted heteroaromatic compounds designed to selectively inhibit hCYP 2A6 in a model system to (a) examine selective hCYP 2A6 inhibitors to decrease cotinine formation in vivo in rats administered with nicotine and (b) examine their efficacy to decrease nicotine self-administration in rats. Methods: Rats were trained to IV self-administer nicotine in 1-h sessions. Nicotine self-administration was carried out at a unit dose of 0.03 mg/kg/infusion in 0.1 ml/s. Pretreatment with substituted heteroaromatic test compounds (0.5-25 mg/kg, i.p., 30 min prior to nicotine self-administration sessions) resulted in dose-dependent decreases of nicotine self-administration. Using operant conditioning techniques, nicotine- vs. food-reinforced responding was evaluated for compounds 10 and 11. Results: Compounds 10 and 11 selectively decreased nicotine self-administration with estimated ED 50 values 4 and 2.8 mg/kg, respectively. Of the test compounds examined, none showed significant affinity for mammalian α4β2- or α7-neuronal nicotinic acetylcholine (nAChR) receptors and none were inhibitors of the human dopamine transporter (hDAT); thus, neither the endogenous nAChRs nor DAT apparently plays a role in decreasing nicotine self-administration for this series of compounds. Conclusion: The results indicate that chemical analogs of nicotine can play a role in nicotine self-administration harm reduction but a non-nAChR and a non-hDAT mechanism are likely involved. © 2012 Springer-Verlag. Source

Goeders N.E.,Louisiana State University Health Sciences Center | Goeders N.E.,Embera NeuroTherapeutics | Cohen A.,Scripps Research Institute | Fox B.S.,Embera NeuroTherapeutics | And 3 more authors.

Rationale: Despite increased education regarding its dangers, cigarette smoking remains a significant public health concern due to serious associated health consequences such as cancer and respiratory and cardiovascular diseases. Most smokers fail in their attempts to quit smoking, and current pharmacological interventions have relatively low levels of efficacy and are associated with significant adverse events. We have previously reported that combinations of metyrapone and oxazepam, administered at doses that were ineffective when delivered singly, resulted in dose-related decreases in cocaine self-administration in rats while not affecting food-maintained responding during the same sessions. Objectives: The current study was designed to test the effects of the administration of a metyrapone:oxazepam combination on nicotine self-administration in rats. Methods: Several dose combinations of metyrapone (12.5, 25 or 50 mg/kg) and oxazepam (5 or 10 mg/kg) were tested in rats trained to intravenously (IV) self-administer nicotine (0.03 mg/kg/infusion) during 1-h self-administration sessions using both fixed-ratio and progressive-ratio (PR) schedules of reinforcement. Results: The administration of low doses of metyrapone and oxazepam in combination significantly decreased IV nicotine self-administration in rats. At the lowest doses of 12.5 mg/kg of metyrapone and 5 mg/kg of oxazepam, the drugs alone did not decrease IV nicotine self-administration, but the combination was effective. Varenicline was also tested using the fixed-ratio schedule, and reductions in nicotine intake were similar to those seen with the moderate dose of the combination. Conclusions: The results of this study suggest a potential utility of the combination of metyrapone and oxazepam for smoking cessation in humans. © 2012 Springer-Verlag. Source

Lockner J.W.,Scripps Research Institute | Lively J.M.,Scripps Research Institute | Collins K.C.,Scripps Research Institute | Vendruscolo J.C.M.,Behavioral Pharma Inc. | And 2 more authors.
Journal of Medicinal Chemistry

A leading nicotine conjugate vaccine was only efficacious for one-third of clinical trial participants, likely due in part to its use of racemic nicotine hapten, (±)-3′-AmNic. Immunization of male Wistar rats with (+)-, (-)-, or (±)-3′-AmNicSucTT and subsequent antibody immunoassays suggest that a vaccine using enantiopure (-)-3′-AmNic hapten imparts superior capacity to bind (-)-nicotine. Future nicotine vaccine clinical candidates must incorporate this design consideration (i.e., hapten enantiopurity) in order to maximize efficacy. © 2014 American Chemical Society. Source

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