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OtherNEUROPHARMACOLOGY

Neuroprotective and Memory-Related Actions of NovelAlpha-7 Nicotinic Agents with Different Mixed Agonist/Antagonist Properties

Edwin M. Meyer, Ee Tein Tay, John A. Zoltewicz, Craig Meyers, Michael A. King, Roger L. Papke and Christopher M. De Fiebre
Journal of Pharmacology and Experimental Therapeutics March 1998, 284 (3) 1026-1032;
Edwin M. Meyer
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Ee Tein Tay
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John A. Zoltewicz
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Craig Meyers
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Michael A. King
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Roger L. Papke
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Christopher M. De Fiebre
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Abstract

The goals of this study were to develop compounds that were selective and highly efficacious agonists at alpha-7 receptors, while varying in antagonist activity; and to test the hypothesis that these compounds had memory-related and neuroprotective actions associated with both agonist and antagonist alpha-7 receptor activities. Three compounds were identified; E,E-3-(cinnamylidene)anabaseine (3-CA), E,E-3-(2-methoxycinnamylidene) anabaseine (2-MeOCA) and E,E-3-(4-methoxycinnamylidene) anabaseine (4-MeOCA) each displaced [125I]α-bungarotoxin binding from rat brain membranes and activated rat alpha-7 receptors in a Xenopus oocyte expression system fully efficaciously. The potency series for binding and receptor activation was 2-MeOCA > 4-MeOCA = 3-CA and 2-MeOCA = 3-CA > 4-MeOCA, respectively. No compound significantly activated oocyte-expressed alpha-4beta-2 receptors. Although each cinnamylidene-anabaseine caused a long-term inhibition ofalpha-7 receptors, as measured by ACh-application 5 min later, this inhibition ranged considerably, from less than 20% (3-CA) to 90% (2-MeOCA) at an identical concentration (10 μM). These compounds improved passive avoidance behavior in nucleus basalis lesioned rats, with 2-MeOCA most potent in this respect. In contrast, only 3-CA was neuroprotective against neurite loss during nerve growth factor deprivation in differentiated rat pheochromocytoma (PC12) cells. Choline, an efficacious alpha-7 agonist without antagonist activity, was also protective in this model. These results suggest that the neurite-protective action of alpha-7 receptor agonists may be more sensitive to potential long-term antagonist properties than acute behavioral actions are.

Footnotes

  • Send reprint requests to: Edwin M. Meyer, Ph.D., Department of Pharmacology and Therapeutics, Box 100267, University of Florida College of Medicine, Gainesville, FL 32610.

  • ↵1 Funded in part by NIH grant AG PO1 10481 and Taiho Pharmaceuticals.

  • Abbreviations:
    DMXB
    GTS-21, E-3-(2,4-dimethoxybenzilidene)anabaseine
    ACh
    acetylcholine
    α-BTX
    α-bungarotoxin
    3-CA
    E,E-3-(cinnamylidene)anabaseine
    2-MeOCA
    E,E-3-(2-methoxycinnamylidene) anabaseine)
    4-MeOCA
    E,E-3-(4-methoxycinnamylidene) anabaseine
    NGF
    nerve growth factor
    HEPES
    N-2-hydroxyethylpiperazine-N′-ethanesulfonic acid
    KRH
    Krebs-Ringer HEPES
    DMAC
    E,E-3-(4-dimethyl aminocinnamylidene) anabaseine
    ANOVA
    analysis of variance
    • Received May 29, 1997.
    • Accepted November 17, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 3
1 Mar 1998
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OtherNEUROPHARMACOLOGY

Neuroprotective and Memory-Related Actions of NovelAlpha-7 Nicotinic Agents with Different Mixed Agonist/Antagonist Properties

Edwin M. Meyer, Ee Tein Tay, John A. Zoltewicz, Craig Meyers, Michael A. King, Roger L. Papke and Christopher M. De Fiebre
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 1026-1032;

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OtherNEUROPHARMACOLOGY

Neuroprotective and Memory-Related Actions of NovelAlpha-7 Nicotinic Agents with Different Mixed Agonist/Antagonist Properties

Edwin M. Meyer, Ee Tein Tay, John A. Zoltewicz, Craig Meyers, Michael A. King, Roger L. Papke and Christopher M. De Fiebre
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 1026-1032;
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