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Abstract

Pharmacological evaluation of Potential Therapeutics on smoking cessation: behavioral and computational analyses

Q.CHANG2, W.MIN2, A.C.HACKETT2, M.T.LANG2, M.BANSAL1, T.HANANIA1
1PsychoGenics Inc., Tarrytown, NY, USA; 2PsychoGenics Inc., Montvale, NJ, USA

This project evaluated the utility of various reference compounds with diverse mechanisms of action as potential treatments for smoking cessation using drug discrimination (DD) and nicotine self-administration (SA) tests. We screened eighteen compounds alone or in combinations to evaluate their efficacy in smoking cessation. Using bioinformatics analysis on these behavioral data we ranked each compound based on its relative effectiveness and calculated its efficacy score. Our results identified Cytisine (an α4β2 receptor agonist) at 3 mg/kg, bPiDI (an α6β2 receptor agonist) at 3 mg/kg and the combination of Metyrapone (a corticosteroid synthesis blocker, 12.5 and 25 mg/kg) and Oxazepam (a benzodiazepine, 5 and 10 mg/kg) to be efficacious in disrupting nicotine discrimination. In the self-administration assay, Baclofen (a GABAB agonist) 3 mg/kg, BHF 117 (a GABAB receptor modulator) 30 mg/kg and MTEP (a mGlu5 antagonist) 3 mg/kg significantly attenuated nicotine self-administration. In addition, being ACh receptor agonists, both Cytisine (3 mg/kg) and bPiDI (3 mg/kg) attenuated nicotine self-administration and showed efficacy in substituting for nicotine in DD model. Put together, our studies identified, among the compounds we have studied, Cytisine and bPiDI to be the best candidates for smoking cessation. Both these compounds displayed efficacy in substituting for nicotine in DD model, caused disruption of nicotine DD as well showed efficacy in suppressing nicotine self-administration. The efficacies of combinations of Metyrapone and Oxazepam, as well as Baclofen, BHF 177 and MTEP will needs to be further evaluated due to their strong efficacy in suppressing nicotine DD or nicotine SA, respectively.

(This project was sponsored by NIDA Grant Number R44DA035051. We thank Dr. Neil Paterson and Dr. Daniela Brunner for their help during the studies.)

 

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