title: N-n-alkylnicotinium analogs, a novel class of antagonists at alpha 4 beta 2* nicotinic acetylcholine receptors: inhibition of S(-)-nicotine-evoked 86Rb+ efflux from rat thalamic synaptosomes.
abstract: Pyridine N-n-alkylation of S(-)-nicotine (NIC) affords N-n-alkylnicotinium analogs, previously shown to competitively inhibit [(3)H]NIC binding and interact with alpha4beta2* nicotinic receptors (nAChRs). The present study determined the ability of the analogs to inhibit NIC-evoked (86)Rb(+) efflux from rat thalamic synaptosomes to assess functional interaction with alpha4beta2* nAChRs. In a concentration-dependent manner, NIC evoked (86)Rb(+) efflux (EC(50) = 170 nmol/L). Analog-induced inhibition of NIC-evoked (86)Rb(+) efflux varied over a approximately 450-fold range. Analogs with long n-alkyl chain lengths (C(9)-C(12)) inhibited efflux in the low nmol/L range (IC(50) = 9-20 nmol/L), similar to dihydro-beta-erythroidine (IC(50) = 19 nmol/L). Compounds with shorter n-alkyl chain lengths (C(1)-C(8)) produced inhibition in the low micromol/L range (IC(50) = 3-12 micromol/L). C(10) and C(12) analogs completely inhibited NIC-evoked efflux, whereas C(1-9) analogs produced maximal inhibition of only 10% to 60%. While the C(10) analog N-n-decylnicotinium iodide (NDNI) did not produce significant inhibition of NIC-evoked dopamine release in previously reported studies, NDNI possesses high affinity for [(3)H]NIC binding sites (K(i) = 90 nmol/L) and is a potent and efficacious inhibitor of NIC-evoked (86)Rb(+) efflux as demonstrated in the current studies. Thus, NDNI is a competitive, selective antagonist at alpha4beta2* nAChRs.
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: Dennis K
authors.initials: DK
authors.lastname: Miller
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: D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D009538:Nicotine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012414:Rubidium Radioisotopes / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D012414:Rubidium Radioisotopes; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine