Highly Selective and Potent ?4?2 nAChR Antagonist Inhibits Nicotine Self-Administration and Reinstatement in Rats.

ABSTRACT: The ?4?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 ?4?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 ?4?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 ?4?2 nAChR, with IC50 values of approximately 10 nM, but are weak agonists in cells containing ?3?4 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.

SUBMITTER: Wu J 

PROVIDER: S-EPMC6697865 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature