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

The
α4β2 nAChR is the most predominant subtype in the
brain and is a well-known culprit for nicotine addiction. Previously
we presented a series of α4β2 nAChR selective compounds
that were discovered from a mixture-based positional-scanning combinatorial
library. Here we report further optimization identified highly potent
and selective α4β2 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 α4β2
nAChR, with IC50 values of approximately 10 nM, but are
weak agonists in cells containing α3β4 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.