N-n-Alkylnicotinium and N-n-Alkylpyridinium Analogs Inhibit the Dopamine Transporter: Selectivity as Nicotinic Receptor Antagonists

J. Zhu, P. A. Crooks, J. T. Ayers, S. P. Sumithran, Linda P. Dwoskin

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


N-n-Alkylnicotinium and N-n-alkylpyridinium analogs act as antagonists at nicotinic acetylcholine receptors (nAChRs) mediating nicotine-evoked [ 3H]dopamine (DA) overflow from superfused rat striatal slices in the presence of a DA transporter (DAT) inhibitor. However, the potential interaction of these nAChR antagonists with DAT has not been evaluated. In the present study, analog inhibition of [3H]DA uptake into striatal synaptosomes and inhibition of [3H]GBR 12935 binding to striatal membranes was determined. N-n-Alkylnicotinium analogs with n-alkyl chains of C6-12 and N-n-alkylpyridinium analogs with n-alkyl chains of C 7-20 inhibited [3H]DA uptake with a wide affinity range. With the exception of the C20 N-n-alkylpyridinium, a linear relationship between chain length and inhibition of [3H]DA uptake was found in both analog series. Similarly, these analogs inhibited [ 3H]GBR 12935 binding (Ki=5.7-250 μM), and a linear relationship with chain length was observed, with the exception of the C 8 N-n-alkylnicotinium analog. Kinetic analyses of inhibition of [3H]DA uptake and [3H]GBR 12935 binding using representative C12 analogs from each series revealed decreases in maximal [3H]DA transport velocity and maximal [3H]GBR 12935 binding without alterations in affinity, indicating noncompetitive interactions with DAT. In comparison, classical nAChR antagonists (mecamylamine, dihydro-β-erythroidine and methyllycaconitine) did not inhibit [ 3H]DA uptake or [3H]GBR 12935 binding. Moreover, inhibition of DAT function occurred at analog concentrations 10-120-fold higher than those inhibiting nAChR function. Taken together with the inability of these analogs to inhibit field-stimulation-evoked [3H]DA overflow, the results indicate that these analogs act selectively as antagonists at nAChRs mediating nicotine-evoked [3H]DA overflow.

Original languageEnglish
Pages (from-to)270-284
Number of pages15
JournalDrug Development Research
Issue number4
StatePublished - Dec 2003


  • Dopamine transporter
  • Dopamine uptake
  • GBR 12935 binding
  • Neuronal nicotinic receptor
  • Nicotine analog

ASJC Scopus subject areas

  • Drug Discovery


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