Evaluation of Novel Epibatidine Analogs in Rats Discriminating Nicotine

Abstract

Tobacco use is a persistent public health issue. One of every three cancer deaths is linked to tobacco use, including nearly 90% of all deaths related to lung cancer. Nicotine is the primary psychoactive component in tobacco, and nicotine has been identified as the primary compound responsible for maintaining tobacco dependence in humans. Drug discrimination is a pharmacologically selective bioassay, utilized in the past for elucidating the receptor pharmacology of nicotine. If a test compound shares discriminative stimulus effects with nicotine, then it might serve as an effective substitution pharmacotherapy. Epibatidine reliably substitutes for nicotine in the drug discrimination assay, but has a side‐effect profile that limits its therapeutic potential. Thus, considerable efforts are underway to produce derivatives of epibatidine. Here we tested three epibatidine derivatives, 2′‐fluoro‐3′‐(4‐nitrophenyl)deschloroepibatidine (RTI‐7527‐102; i.e., RTI‐102), 2′‐fluorodeschloroepibatidine (RTI‐7527‐36; i.e., RTI‐36), and 3′‐(3″‐dimethylaminophenyl)‐epibatidine (RTI‐7527‐76; i.e., RTI‐76). A total of 4 male and 4 female Sprague‐Dawley rats were trained on a fixed‐ratio 10 schedule to discriminate nicotine (0.32 mg/kg base) from vehicle. All compounds dose‐dependently substituted for nicotine, without significant decreases in response rates. The rank‐order potency in the discrimination assay was RTI‐36 > nicotine > RTI‐102 > RTI‐76. There is abundant evidence that the α4β2* subtype is of particular importance to the abuse potential of nicotine. Thus, we examined the relative contribution of the β2 subunit with the antagonist by dihydro‐β‐erythroidine (DHβE). DHβE antagonized the discriminative stimulus effects of nicotine. However, relative to antagonism of nicotine, DHβE produced less antagonism of RTI‐102, RTI‐36 and RTI‐76. Thus, it is likely that RTI‐102, RTI‐36 and RTI‐76 possess differing activity at nicotinic receptor subunits.Support or Funding InformationThis work was supported by the National Institutes of Health National Institute on Drug Abuse [DA25267] and [DA48353].