Elsevier

Neuropharmacology

Volume 34, Issue 6, June 1995, Pages 583-590
Neuropharmacology

General paper
Human α 7 nicotinic acetylcholine receptor responses to novel ligands

https://doi.org/10.1016/0028-3908(95)00028-5Get rights and content

Abstract

Responses of the human α 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 Ca2+-dependent chloride currents. The effect of (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxa-zole (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 μM and 83 ± 10 μM, respectively). ABT-418 also was an agonist, 3-fold less potent and 75% as efficacious as (−)nicotine (EC50 = 264 ± 34 μM). GTS-21, in contrast, inhibited the response to (−)nicotine at concentrations ≤ 10 μM and itself elicited only a small response at higher concentrations (12% of the (−)nicotine response at 1 mM). Reversible blockade by methyllycaconitine (10nM) corroborated the responses as due to activation of α 7 nAChR. This represents the first characterization of human α 7 nAChR responses to these novel nicotinic agonists.

References (41)

  • V. Luntz-Leybman et al.

    Cholinergic gating of response to auditory stimuli in rat hippocampus

    Brain Res.

    (1992)
  • R.L. Papke

    The kinetic properties of neuronal nicotinic receptors: Genetic basis of functional diversity

    Prog. Neurobiol.

    (1993)
  • S.B. Sands et al.

    Barium permeability of neuronal nicotinic receptor α 7 expressed in Xenopus oocytes

    Biophys. J.

    (1993)
  • D.S. Woodruff-Pak et al.

    A nicotinic agonist (GTS-21), eyeblink classical conditioning, and nicotinic receptor binding in rabbit brain

    Brain Res.

    (1994)
  • J.B. Acri et al.

    Nicotine increases sensory gating measured as inhibition of the acoustic startle reflex in rats

    Psychopharmac., Berlin

    (1994)
  • M. Alkondon et al.

    Enantiomers of epibatidine as potent nicotinic agonists at two identified subtypes of nicotinic acetylcholine receptors in rat hippocampal neurons

    Soc. Neurosci. Abstr.

    (1994)
  • M. Alkondon et al.

    Blockade of nicotinic currents in hippocampal neurons defines methyllycaconitine as a potent and specific receptor antagonist

    Molec. Pharmac.

    (1992)
  • M. Alkondon et al.

    Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons. I. Pharmacological and functional evidence for distinct structural subtypes

    J. Pharmac. Exp. Ther.

    (1993)
  • R. Anand et al.

    Pharmacological characterization of alpha-bungarotoxin-sensitive acetylcholine-receptors immunoisolated from chick retina—contrasting properties of alpha-7-subunit-containing and alpha-8-subunit-containing subtypes

    Molec. Pharmac.

    (1993)
  • S.P. Arneric et al.

    (S)-3-Methyl-5-(1-methyl-2-pyrro-lidinyl) isoxazole (ABT 418): A novel cholinergic ligand with cognition-enhancing and anxiolytic activities: IIn vitro characterization

    J. Pharmac. Exp. Ther.

    (1994)
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