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: C A Briggs, D G McKenna, M Piattoni-Kaplan
• Journal: Neuropharmacology (Neuropharmacology) Vol. 34 Issue 6 Pg. 583-90 (Jun 1995) ISSN: 0028-3908 [Print] England
• PMID: 7566493 (Publication Type: Journal Article)

Chemical References

• Anti-Anxiety Agents
• Benzylidene Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Chloride Channels
• Isoxazoles
• Ligands
• Nicotinic Agonists
• Pyridines
• Pyrrolidines
• RNA, Messenger
• Receptors, Nicotinic
• 3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole
• Barium
• 3-(2,4-dimethoxybenzylidene)anabaseine
• epibatidine
• Calcium

Topics

• Anti-Anxiety Agents (pharmacology)
• Barium (pharmacology)
• Benzylidene Compounds (pharmacology)
• Binding, Competitive
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Calcium (pharmacology)
• Chloride Channels (drug effects)
• Dose-Response Relationship, Drug
• Humans
• Isoxazoles (pharmacology)
• Ligands
• Membrane Potentials (drug effects)
• Nicotinic Agonists (pharmacology)
• Oocytes (drug effects)
• Patch-Clamp Techniques
• Pyridines (pharmacology)
• Pyrrolidines (pharmacology)
• RNA, Messenger (biosynthesis)
• Receptors, Nicotinic (drug effects)