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N‐n ‐alkylnicotinium and N‐n ‐alkylpyridinium analogs inhibit the dopamine transporter: Selectivity as nicotinic receptor antagonists
Author(s) -
Zhu J.,
Crooks P. A.,
Ayers J. T.,
Sumithran S. P.,
Dwoskin L. P.
Publication year - 2003
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.10328
Subject(s) - chemistry , nicotinic agonist , stereochemistry , methyllycaconitine , mecamylamine , dopamine transporter , dopamine , transporter , biochemistry , receptor , nicotinic acetylcholine receptor , biology , endocrinology , gene
N‐n ‐Alkylnicotinium and N‐n ‐alkylpyridinium analogs act as antagonists at nicotinic acetylcholine receptors (nAChRs) mediating nicotine‐evoked [ 3 H]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 [ 3 H]DA uptake into striatal synaptosomes and inhibition of [ 3 H]GBR 12935 binding to striatal membranes was determined. N‐n ‐Alkylnicotinium analogs with n ‐alkyl chains of C 6–12 and N‐n ‐alkylpyridinium analogs with n ‐alkyl chains of C 7–20 inhibited [ 3 H]DA uptake with a wide affinity range. With the exception of the C 20 N‐n ‐alkylpyridinium, a linear relationship between chain length and inhibition of [ 3 H]DA uptake was found in both analog series. Similarly, these analogs inhibited [ 3 H]GBR 12935 binding ( K i =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 [ 3 H]DA uptake and [ 3 H]GBR 12935 binding using representative C 12 analogs from each series revealed decreases in maximal [ 3 H]DA transport velocity and maximal [ 3 H]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 [ 3 H]DA uptake or [ 3 H]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 [ 3 H]DA overflow, the results indicate that these analogs act selectively as antagonists at nAChRs mediating nicotine‐evoked [ 3 H]DA overflow. Drug Dev. Res. 60:270–284, 2003. © 2003 Wiley‐Liss, Inc.