N-n-alkylpyridinium analogs, a novel class of nicotinic receptor antagonists: selective inhibition of nicotine-evoked [3H] dopamine overflow from superfused rat striatal slices

J Pharmacol Exp Ther. 2003 Sep;306(3):1011-20. doi: 10.1124/jpet.103.051789. Epub 2003 May 23.


Structural simplification of N-n-alkylnicotinium analogs, antagonists at neuronal nicotinic acetylcholine receptors (nAChRs), was achieved by removal of the N-methylpyrrolidino moiety affording N-n-alkylpyridinium analogs with carbon chain lengths of C1 to C20. N-n-Alkylpyridinium analog inhibition of [3H]nicotine and [3H]methyllycaconitine binding to rat brain membranes assessed interaction with alpha4beta2* and alpha7* nAChRs, respectively, whereas inhibition of nicotine-evoked 3H overflow from [3H]dopamine ([3H]DA)-preloaded rat striatal slices assessed antagonist action at nAChR subtypes mediating nicotine-evoked DA release. No inhibition of [3H]methyllycaconitine binding was observed, although N-n-alkylpyridinium analogs had low affinity for [3H]nicotine binding sites, i.e., 1 to 3 orders of magnitude lower than that of the respective N-n-alkylnicotinium analogs. These results indicate that the N-methylpyrrolidino moiety in the N-n-alkylnicotinium analogs is a structural requirement for potent inhibition of alpha4beta2* nAChRs. Importantly, N-n-alkylpyridinium analogs with n-alkyl chains < C10 did not inhibit nicotine-evoked [3H]DA overflow, whereas analogs with n-alkyl chains ranging from C10 to C20 potently and completely inhibited nicotine-evoked [3H]DA overflow (IC50 = 0.12-0.49 microM), with the exceptions of N-n-pentadecylpyridinium bromide (C15) and N-n-eicosylpyridinium bromide (C20), which exhibited maximal inhibition of approximately 50%. The mechanism of inhibition of a representative analog of this structural series, N-n-dodecylpyridinium iodide, was determined by Schild analysis. Linear Schild regression with slope not different from unity indicated competitive antagonism at nAChRs mediating nicotine-evoked [3H]DA overflow and a KB value of 0.17 microM. Thus, the simplified N-n-alkylpyridinium analogs are potent, selective, and competitive antagonists of nAChRs mediating nicotine-evoked [3H]DA overflow, indicating that the N-methylpyrrolidino moiety is not a structural requirement for interaction with nAChR subtypes mediating nicotine-evoked DA release.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aconitine / analogs & derivatives*
  • Aconitine / pharmacology*
  • Animals
  • Brain / cytology
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism
  • Dopamine / metabolism*
  • In Vitro Techniques
  • Nicotine / pharmacology
  • Nicotinic Antagonists / pharmacology*
  • Pyridinium Compounds / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Nicotinic / metabolism*
  • Tritium


  • Nicotinic Antagonists
  • Pyridinium Compounds
  • Receptors, Nicotinic
  • Tritium
  • Laurosept
  • methyllycaconitine
  • Nicotine
  • Dopamine
  • Aconitine