Human alpha 7 nicotinic acetylcholine receptor responses to novel ligands

Neuropharmacology. 1995 Jun;34(6):583-90. doi: 10.1016/0028-3908(95)00028-5.

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.

MeSH terms

  • 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*

Substances

  • 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