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

Marharyta Pivavarchyk, Andrew M. Smith, Zhenfa Zhang, Dejun Zhou, Xu Wang, Naoki Toyooka, Hiroshi Tsuneki, Toshiyasu Sasaoka, J. Michael McIntosh, Peter A. Crooks, Linda P. Dwoskin

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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, 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 (IC 50 = 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.

Original languageEnglish
Pages (from-to)132-139
Number of pages8
JournalEuropean Journal of Pharmacology
Volume658
Issue number2-3
DOIs
StatePublished - May 11 2011

Bibliographical note

Funding Information:
The research reported was supported by NIH grant U19 DA17548 (L.P.D.), T32 DA007304 (A.M.S.), R01 MH53631 and P01 GM48677 (J.M.M.), The Research Foundation for Pharmaceutical Sciences of Japan (N.T.), the Smoking Research Foundation (Japan; H.T.), and grant-aid (No. 17590004 ) for Scientific Research by the Ministry of Education, Culture, Sports, Science, and Technology of the Japanese Government (N.T.).

Keywords

  • Antagonist
  • Dopamine
  • Dopamine release
  • Indolizidine (-)-235B′
  • Nicotine
  • Nicotinic acetylcholine receptor

ASJC Scopus subject areas

  • Pharmacology

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