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 (IC50 = 42 nM, Imax = 55%). Compound (−)-237D, the double bond-reduced analog, afforded the greatest inhibitory potency (IC50 = 0.18 nM, Imax = 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 (IC50 = 413 nM, Imax = 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.