N-n-alkylicotinium analogs,a novelclass of nicotinic receptor antagonist:inhibition of S(-)-nicotine-evoked [~3H]dopamine overflow from superfused rat striatal slices

摘要

The structure of the S(-)-nicotinemolecule was modified viaN-n-alkylation of te pyridine-N atomtoafford a series of N-n-alkylnicotinium iodide salts with carbon chain lengths varying between C_1 and C-(12).The ability of these analogs to evoke [~3H] overflow and inhibit S(-)-nicotine-evoked [~3H]overflow from [~3H]dopamine ([~3H]DA)ppreloaded rat striatal slices was determined.At high concentrations,analogs with chain lengths >=C_6 evoked [~3H] overflow.Specifically,N-n-decylnicothinium iodide (NDNI;C_(10) evoked significant [~3H] overflow at 1 #mu#M,and N-n-dodecylnicotinium iodide (NDDNI;C_(12)) at 10 #mu#M,and N-heptylnicotiniumiodide (NHPnil;C_7),and N-n-hexylnicotinium iodide (C_6) evoked [~3H]overflow at 100 #mu#M.Thus,intrinsic activity at these concentrations prohibited assessment of inhibitory activity.The most potent N-n-alkylnicotinium analog to inhibit S(-)-nicotine-evoked [~3H]overflow was NDDNI,with an IC_(50) value of 9nM.NHpNI,NONI,and N-n-nonylnicotinium iodide(C_9) also inhibited S(-)-nicotine-evoked [~3H]overflow with IC_(50) values of 0.80,0.62,and 0.21 #mu#M,respectivley.Incomparison,the competitive neuronal nicotinic acetylcholine receptor (nAChR) antagonist,dihydro-#beta#-erythroidine,had an IC_(50) of 14.6 #mu#M.A sifnificant corrleation of N-n-alkyl chainlength with analog-induced inhibition was observed,with te exception of NDNI,which was devoid of inhibitory activity.The mechanism of N-n-alkylnicothinium-induced inhibition of the high--affinity,low capacity component of S(-)-nicotine-evoked [~3H] overflow was determined via Schild analysis,using the representative analog,NONI.Linear Schilf regression and slope not different from unitysuggested that NONI copetitively interacts with a single nAChR subtype to inhibit S(-)-nicotine-evoked [~3H]DA release.Thus,mofidication of the S(-)-nicotine molecule converts this agonist into an antagonist at nACRs,mediating S(-)-nicotine-evoked DA release in striatum.