Abstract
3-(2,4-dimethoxybenzylidene)anabaseine (GTS-21) is a selective partial agonist for rat alpha-7 nicotine receptors with reportedly much lower efficacy for human alpha-7 receptors. Because this drug improves memory-related performance in nonhuman primates, and is presently in a clinical trial for Alzheimer’s disease, we investigated the potential effects of its primary human metabolite, 3-(4-hydroxy, 2-methoxy-benzylidene)anabaseine) on human as well as rat nicotinic acetylcholine receptor. 4OH-GTS-21 exhibited a similar level of efficacy for both rat and human alpha-7 receptors expressed in Xenopus oocytes. It displaced high affinity [125I]α-bungarotoxin binding to human SK-N-SH cell-membranes (Ki 0.17 μM) and rat PC12 cell-membranes (Ki 0.45 μM). GTS-21 also displaced [125I]α-bungarotoxin binding to PC12 cell membranes with high potency (Ki 0.31 μM), but was much less potent in this regard in SK-N-SH cells (23 μM). 4OH-GTS-21 produced less residual inhibition of either the human or rat AChR subtypes than GTS-21 did. To compare the neuroprotective efficacies of GTS-21 and 4OH-GTS-21 in both species, an amyloid-toxicity model (Aβ 25-35) was used. 4OH-GTS-21 was protective in both human and rat cell lines, although GTS-21 was effective only in the latter. These studies suggest that the efficacy of GTS-21 in primates may depend on a pro-drug function.
Footnotes
-
Send reprint requests to: Dr. Roger L. Papke, Department of Pharmacology and Therapeutics, Box 100267 JHMHSC, University of Florida, Gainesville, FL 32610-0267.
-
↵1 This study was supported by Grant NIA P01 10485 from Taiho Pharmaceuticals and National Institutes of Health Grant NS32888.
- Abbreviations:
- GTS-21
- 3-(2,4-dimethoxybenzylidene)anabaseine
- 4OH-GTS-21
- 3-(4-hydroxy, 2-methoxybenzylidene)anabaseine
- ACh
- acetylcholine
- AChR
- nicotinic acetylcholine receptor
- BTX
- bungarotoxin
- PC12
- pheochromocytoma 12
- Received March 12, 1998.
- Accepted July 5, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|