Highly Selective and Potent α4β2 nAChR Antagonist Inhibits Nicotine Self-Administration and Reinstatement in Rats

The alpha 4 beta 2 nAChR is the most predominant subtype in the brain and is a well-known culprit for nicotine addiction. Previously we presented a series of alpha 4 beta 2 nAChR selective compounds that were discovered from a mixture-based positional-scanning combinatorial library. Here we report further optimization identified highly potent and selective alpha 4 beta 2 nAChR antagonists 5 (AP-202) and 13 (AP-211). Both compounds are devoid of in vitro agonist activity and are potent inhibitors of epibatidine-induced changes in membrane potential in cells containing alpha 4 beta 2 nAChR, with IC50 values of approximately 10 nM, but are weak agonists in cells containing alpha 4 beta 2 nAChR. In vivo studies show that 5 can significantly reduce operant nicotine self-administration and nicotine relapse-like behavior in rats at doses of 0.3 and 1 mg/kg. The pharmacokinetic data also indicate that 5, via sc administration, is rapidly absorbed into the blood, reaching maximal concentration within 10 min with a half-life of less than 1 h.