title: N-n-alkylnicotinium analogs, a novel class of nicotinic receptor antagonist: inhibition of S(-)-nicotine-evoked [(3)H]dopamine overflow from superfused rat striatal slices.
abstract: The structure of the S(-)-nicotine molecule was modified via N-n-alkylation of the pyridine-N atom to afford 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 [(3)H] overflow and inhibit S(-)-nicotine-evoked [(3)H] overflow from [(3)H]dopamine ([(3)H]DA)-preloaded rat striatal slices was determined. At high concentrations, analogs with chain lengths > or =C(6) evoked [(3)H] overflow. Specifically, N-n-decylnicotinium iodide (NDNI; C(10)) evoked significant [(3)H] overflow at 1 microM, and N-n-dodecylnicotinium iodide (NDDNI; C(12)) at 10 microM, whereas N-n-octylnicotinium iodide (NONI; C(8)), N-n-heptylnicotinium iodide (NHpNI; C(7)), and N-n-hexylnicotinium iodide (C(6)) evoked [(3)H] overflow at 100 microM. Thus, intrinsic activity at these concentrations prohibited assessment of inhibitory activity. The most potent N-n-alkylnicotinium analog to inhibit S(-)-nicotine-evoked [(3)H] overflow was NDDNI, with an IC(50) value of 9 nM. NHpNI, NONI, and N-n-nonylnicotinium iodide (C(9)) also inhibited S(-)-nicotine-evoked [(3)H] overflow with IC(50) values of 0.80, 0.62, and 0.21 microM, respectively. In comparison, the competitive neuronal nicotinic acetylcholine receptor (nAChR) antagonist, dihydro-beta-erythroidine, had an IC(50) of 1.6 microM. A significant correlation of N-n-alkyl chain length with analog-induced inhibition was observed, with the exception of NDNI, which was devoid of inhibitory activity. The mechanism of N-n-alkylnicotinium-induced inhibition of the high-affinity, low-capacity component of S(-)-nicotine-evoked [(3)H] overflow was determined via Schild analysis, using the representative analog, NONI. Linear Schild regression and slope not different from unity suggested that NONI competitively interacts with a single nAChR subtype to inhibit S(-)-nicotine-evoked [(3)H]DA release (K(i) value = 80.2 nM). Thus, modification of the S(-)-nicotine molecule converts this agonist into an antagonist at nAChRs, mediating S(-)-nicotine-evoked DA release in striatum.
authors.affiliation: College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
authors.forename: Lincoln H
authors.initials: LH
authors.lastname: Wilkins
authors.forename: Aaron
authors.initials: A
authors.lastname: Haubner
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Ayers
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
mesh_terms: D000478:Alkylation; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D009538:Nicotine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000737:chemistry / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D013237:Stereoisomerism
chemical_list: C403088:N-n-decylnicotinium; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C070297:N'-methylnicotinium; D009538:Nicotine; D004298:Dopamine