N‐n‐alkylnicotinium and N‐n‐alkylpyridinium analogs inhibit the dopamine transporter: Selectivity as nicotinic receptor antagonists

Abstract

AbstractN‐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 C7–20 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 C8 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. Drug Dev. Res. 60:270–284, 2003. © 2003 Wiley‐Liss, Inc.