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
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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.
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↵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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