title: Human alpha 7 nicotinic acetylcholine receptor responses to novel ligands.
abstract: Responses of the human alpha 7 nicotinic acetylcholine receptor (nAChR) in Xenopus laevis oocytes were quantified using two-electrode voltage clamp in the presence of barium (10 mM) to block secondary activation of Ca(2+)-dependent chloride currents. The effect of (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole (ABT-418) and (2,4)-dimethoxybenzylidene anabaseine (GTS-21), two potential compounds for the treatment of Alzheimer's Disease, and of the natural product (+/-)epibatidine were compared to (-)nicotine. (+/-)Epibatidine acted as an agonist and was 64-fold more potent than (-) nicotine (EC50s = 1.30 +/- 0.11 microM and 83 +/- 10 microM, respectively). ABT-418 also was an agonist, 3-fold less potent and 75% as efficacious as (-)nicotine (EC50 = 264 +/- 34 microM). GTS-21, in contrast, inhibited the response to (-)nicotine at concentrations < or = 10 microM and itself elicited only a small response at higher concentrations (12% of the (-)nicotine response at 1 mM). Reversible blockade by methyllycaconitine (10 nM) corroborated the responses as due to activation of alpha 7 nAChR. This represents the first characterization of human alpha 7 nAChR responses to these novel nicotinic agonists.
authors.affiliation: Abbott Laboratories, Abbott Park, IL 60064, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Briggs
authors.forename: D G
authors.initials: DG
authors.lastname: McKenna
authors.forename: M
authors.initials: M
authors.lastname: Piattoni-Kaplan
mesh_terms: D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001464:Barium / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000494:pharmacology; D001667:Binding, Competitive; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D018118:Chloride Channels / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D018722:Nicotinic Agonists / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011978:Receptors, Nicotinic / Q000187:drug effects*
chemical_list: D014151:Anti-Anxiety Agents; D001597:Benzylidene Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D007555:Isoxazoles; D008024:Ligands; D018722:Nicotinic Agonists; D011725:Pyridines; D011759:Pyrrolidines; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; D001464:Barium; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; C082748:epibatidine; D002118:Calcium