Synthesis and evaluation of conformationally restricted pyridino N-alkylated nicotine analogs as nicotinic acetylcholine receptor antagonists

Rui Xu, Linda P. Dwoskin, Vladimir Grinevich, Sangeetha P. Sumithran, Peter A. Crooks

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Previous work has shown that quaternization of the pyridine-N atom of S-(-)-nicotine (NIC) affords compounds such as N-n-octylnicotinium iodide (NONI) and N-n-decylnicotinium iodide (NDNI) that act as competitive nicotinic acetylcholine receptor (nAChR) antagonists at α3β2* and α4β2* subtypes, respectively. To ascertain the rotameric preference about the C3-C2′ bond of NONI and NDNI for interaction with several nAChR subtypes, two classes of bridged analogs representing extreme rotameric conformations (syn and anti) of NONI and NDNI were synthesized. NIC-evoked [3H]dopamine ([3H]DA) release from superfused rat striatal slices was used to determine the activity of the analogs at the α3β2* nAChR. [3H]NIC and [3H]methyllycaconitine ([3H]MLA) binding to rat brain membranes were used to determine affinity for α4β2* and α7* nAChRs, respectively. With the exception of BCDD (IC50 value = 1,580 nM), all analogs potently and selectively inhibited NIC-evoked [3H]DA release (IC50 values = 30-660 nM), indicating antagonism of α3β2* nAChRs. None of the analogs inhibited either [3H]NIC or [3H]MLA binding, indicating a lack of interaction with α4β2* and α7* nAChR subtypes. Interestingly, the C10 N-alkyl chain analogs, ACD and BCD, had negligible affinity for the α4β2* subtype compared to the high affinity exhibited by NDNI, suggesting that the α4β2* subtype does not recognize the unique stereochemistry of these conformationally restricted analogs. Thus, conformational restriction of N-n-alkylnicotinium iodides eliminated inhibitory activity at α4β2* nAChRs, but more importantly afforded high affinity and selectivity for α3β2* nAChRs. Conformational restriction of N-n-alkyl analogs of NIC appears to be a viable approach for the development of α3β2*-selective nAChR antagonists.

Original languageEnglish
Pages (from-to)173-186
Number of pages14
JournalDrug Development Research
Issue number3
StatePublished - 2002


  • Brain
  • Dopamine release
  • Nicotine derivatives
  • Striatum
  • α3β2 nicotinic receptor
  • α4β2 nicotinic receptor

ASJC Scopus subject areas

  • Drug Discovery


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