Indolizidine (-)-235B′ and related structural analogs: Discovery of nicotinic receptor antagonists that inhibit nicotine-evoked [ ³H]dopamine release

Although several therapeutic agents are available to aid in tobacco smoking cessation, relapse rates continue to be high, warranting the development of alternative pharmacotherapies. Nicotine-evoked dopamine release from its presynaptic terminals in the central nervous system leads to reward which maintains continued tobacco use. The ability of indolizidine (-)-235B′ and a sub-library of structurally related analogs to inhibit nicotine-evoked [ ³H]dopamine release from rat striatal slices was determined in the current study. Indolizidine (-)-235B′ inhibited nicotine-evoked [ ³H]dopamine release in a concentration-dependent manner (IC ₅₀ = 42 nM, I_max = 55%). Compound (-)-237D, the double bond-reduced analog, afforded the greatest inhibitory potency (IC₅₀ = 0.18 nM, I_max = 76%), and was 233-fold more potent than indolizidine (-)-235B′. The des-8-methyl aza-analog of indolizidine (-)-235B′, ZZ-272, also inhibited nicotine-evoked [³H]dopamine release (IC ₅₀ = 413 nM, I_max = 59%). Concomitant exposure to maximally effective concentrations of indolizidine (-)-235B′, ZZ-272 or (-)-237D with a maximally effective concentration of α-conotoxin MII, a selective antagonist for α6β2-containing nicotinic receptors, resulted in inhibition of nicotine-evoked [³H]dopamine release no greater than that produced by each compound alone. The latter results suggest that indolizidine (-)-235B′, (-)-237D, ZZ-272 and α-conotoxin MII inhibit the same α-conotoxin MII-sensitive nicotinic receptor subtypes. Thus, indolizidine (-)-235B′ and its analogs act as antagonists of α6β2-nicotinic receptors and constitute a novel structural scaffold for the discovery of pharmacotherapies for smoking cessation.