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*ANABASINE

Vol. 287, Issue 3, 918-925, December 1998

Analysis of 3-(4-Hydroxy, 2-Methoxybenzylidene)Anabaseine Selectivity and Activity at Human and Rat Alpha-7 Nicotinic Receptors1

Edwin M. Meyer, Alexander Kuryatov, Volodymyr Gerzanich, Jon Lindstrom and Roger L. Papke

Department of Pharmacology and Therapeutics (E.M.M., R.L.P.), University of Florida, Gainesville, Florida and Department of Neuroscience (A.K., V.G., J.L.), University of Pennsylvania, Philadelphia, Pennsylvania

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]alpha -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]alpha -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 (Abeta 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.

0022-3565/98/2873-0918$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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