title: Analysis of 3-(4-hydroxy, 2-Methoxybenzylidene)anabaseine selectivity and activity at human and rat alpha-7 nicotinic receptors.
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]alpha-bungarotoxin binding to human SK-N-SH cell-membranes (Ki 0.17 microM) and rat PC12 cell-membranes (Ki 0.45 microM). GTS-21 also displaced [125I]alpha-bungarotoxin binding to PC12 cell membranes with high potency (Ki 0.31 microM), but was much less potent in this regard in SK-N-SH cells (23 microM). 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.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Meyer
authors.forename: A
authors.initials: A
authors.lastname: Kuryatov
authors.forename: V
authors.initials: V
authors.lastname: Gerzanich
authors.forename: J
authors.initials: J
authors.lastname: Lindstrom
authors.forename: R L
authors.initials: RL
authors.lastname: Papke
mesh_terms: D000691:Anabasine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001597:Benzylidene Compounds / Q000378:metabolism / Q000494:pharmacology; D002038:Bungarotoxins / Q000378:metabolism; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018722:Nicotinic Agonists / Q000378:metabolism / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism; D016716:PC12 Cells; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C116666:3-(4-hydroxy-2-methoxybenzylidene)anabaseine; D001597:Benzylidene Compounds; D002038:Bungarotoxins; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; D000691:Anabasine