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pubmed:abstractText |
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 [(3)H]dopamine release from rat striatal slices was determined in the current study. Indolizidine (-)-235B' inhibited nicotine-evoked [(3)H]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 (IC(50)=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 [(3)H]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 ?-conotoxin MII, a selective antagonist for ?6?2-containing nicotinic receptors, resulted in inhibition of nicotine-evoked [(3)H]dopamine release no greater than that produced by each compound alone. The latter results suggest that indolizidine (-)-235B', (-)-237D, ZZ-272 and ?-conotoxin MII inhibit the same ?-conotoxin MII-sensitive nicotinic receptor subtypes. Thus, indolizidine (-)-235B' and its analogs act as antagonists of ?6?2-nicotinic receptors and constitute a novel structural scaffold for the discovery of pharmacotherapies for smoking cessation.
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pubmed:affiliation |
Department of Pharmaceutical Science, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
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pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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