title: bis-Azaaromatic quaternary ammonium analogues: ligands for alpha4beta2* and alpha7* subtypes of neuronal nicotinic receptors.
abstract: A series of bis-nicotinium, bis-pyridinium, bis-picolinium, bis-quinolinium and bis-isoquinolinium compounds was evaluated for their binding affinity at nicotinic acetylcholine receptors (nAChRs) using rat brain membranes. N,N'-Decane-1,12-diyl-bis-nicotinium diiodide (bNDI) exhibited the highest affinity for [(3)H]nicotine binding sites (K(i)=330 nM), but did not inhibit [(3)H]methyllycaconitine binding (K(i) >100 microM), indicative of an interaction with alpha4beta2*, but not alpha7* receptor subtypes, respectively. Also, bNDI inhibited (IC(50)=3.76 microM) nicotine-evoked (86)Rb(+) efflux from rat thalamic synaptosomes, indicating antagonist activity at alpha4beta2* nAChRs. N,N'-Dodecane-1,12-diyl-bis-quinolinium dibromide (bQDDB) exhibited highest affinity for [(3)H]methyllycaconitine binding sites (K(i)=1.61 microM), but did not inhibit [(3)H]nicotine binding (K(i)>100 microM), demonstrating an interaction with alpha7*, but not alpha4beta2* nAChRs. Thus, variation of N-n-alkyl chain length together with structural modification of the azaaromatic quaternary ammonium moiety afforded selective antagonists for the alpha4beta2* nAChR subtype, as well as ligands with selectivity at alpha7* nAChRs.
authors.affiliation: Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Ayers
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.forename: A Gabriela
authors.initials: AG
authors.lastname: Deaciuc
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Grinevich
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018733:Nicotinic Antagonists / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012414:Rubidium Radioisotopes; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001372:Aza Compounds; C579165:Chrna7 protein, rat; D007202:Indicators and Reagents; D008024:Ligands; D018733:Nicotinic Antagonists; D000644:Quaternary Ammonium Compounds; D011978:Receptors, Nicotinic; D012414:Rubidium Radioisotopes; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; C054634:methyllycaconitine; D000157:Aconitine