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Anabaseine Selectivity and Activity at Human and Rat Alpha-7 Nicotinic Receptors1

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Anabaseine Selectivity and Activity at Human and Rat Alpha-7 Nicotinic Receptors1 0022-3565/98/2873-0918$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 287, No. 3 Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 287:918–925, 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 Accepted for publication July 5, 1998 This paper is available online at http://www.jpet.org Downloaded from ABSTRACT m 3-(2,4-dimethoxybenzylidene)anabaseine (GTS-21) is a selec- rat PC12 cell-membranes (Ki 0.45 M). GTS-21 also displaced tive partial agonist for rat alpha-7 nicotine receptors with re- [125I]a-bungarotoxin binding to PC12 cell membranes with high m portedly much lower efficacy for human alpha-7 receptors. potency (Ki 0.31 M), but was much less potent in this regard Because this drug improves memory-related performance in in SK-N-SH cells (23 mM). 4OH-GTS-21 produced less residual nonhuman primates, and is presently in a clinical trial for Alz- inhibition of either the human or rat AChR subtypes than jpet.aspetjournals.org heimer’s disease, we investigated the potential effects of its GTS-21 did. To compare the neuroprotective efficacies of primary human metabolite, 3-(4-hydroxy, 2-methoxy-benzyli- GTS-21 and 4OH-GTS-21 in both species, an amyloid-toxicity dene)anabaseine) on human as well as rat nicotinic acetylcho- model (Ab 25-35) was used. 4OH-GTS-21 was protective in line receptor. 4OH-GTS-21 exhibited a similar level of efficacy both human and rat cell lines, although GTS-21 was effective for both rat and human alpha-7 receptors expressed in Xeno- only in the latter. These studies suggest that the efficacy of pus oocytes. It displaced high affinity [125I]a-bungarotoxin GTS-21 in primates may depend on a pro-drug function. m binding to human SK-N-SH cell-membranes (Ki 0.17 M) and at ASPET Journals on August 8, 2016 Molecular, biochemical and physiological studies demon- vitro (Martin et al., 1994; Meyer et al., 1998a, Shimohama et strate the presence of multiple nicotinic receptor (AChR) al., 1998). These insults include amyloid-exposure, removal subunits in brain and other tissues (Alkondon and Albuquer- of nerve growth factor from differentiated PC12 cells, que, 1993; Deneris et al., 1991; Papke, 1993). One of the NMDA-induced toxicity and axotomy of septal-hippocampal predominant nicotinic receptor subtypes in the brain con- cholinergic neurons. Recently, several selective alpha-7 ago- tains the alpha-7 subunit, especially in telencephalic regions nists with differing residual alpha-7 receptor-antagonist ac- such as hippocampus and neocortex, based on high affinity to tivities were compared relative to their ability to protect BTX binding studies (Clarke et al., 1985; Marks et al., 1986). differentiated PC12 cells from trophic factor deprivation These receptors function as homo-oligomers when expressed (Meyer et al., 1998b). This apparent residual inhibition of in oocytes, where they demonstrate characteristic high affin- alpha-7 receptors most likely represents some form of chan- ity binding to a-BTX, high calcium-permeability and rapid nel block by agonist or a form of desensitization that is desensitization (Couturier et al., 1990; Seguela et al., 1993; unique from the rapidly reversible desensitization that oc- de Fiebre et al., 1995). curs with the application of high concentrations of ACh (de The identification of agents selective for the alpha-7 AChR Fiebre et al., 1995; Papke et al., 1997). Agonists with signif- subtype has drawn attention to their roles in neuronal sur- icant residual antagonism were not cytoprotective, suggest- vival and memory-related behaviors (de Fiebre et al., 1995). ing that an analysis of both agonist and antagonist activities One of these compounds, GTS-21 (also known as DMXB), is may be necessary for predicting the cytoprotective efficacy of presently in a clinical trial for Alzheimer’s disease, based on alpha-7 AChRs. its behavioral actions and ability to protect rat neurons from GTS-21 has also been shown to improve memory-related various apoptotic and necrotic insults, both in vivo and in behaviors in nonhuman primates (Briggs et al., 1997), aged rabbits (Woodruff-Pak et al., 1994), nucleus-basalis lesioned Received for publication March 12, 1998. 1 This study was supported by Grant NIA P01 10485 from Taiho Pharma- rats (Meyer et al., 1994) and aged rats (Arendash et al., ceuticals and National Institutes of Health Grant NS32888. 1995). The improvement in delayed pair-matching behavior 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. 918 1998 Alpha-7 nAChR Activation 919 in aged primates observed after GTS-21 administration is under two electrode voltage clamp at a holding potential of 250 mV. particularly interesting because this drug reportedly is only Recordings were made using a Warner Instruments oocyte amplifier very weakly efficacious at human alpha-7 receptors. Al- interfaced with National Instruments’ (Dallas, Texas) LabView soft- though this result may indicate that nonnicotinic receptors ware. Current electrodes were filled with 250 mM CsCl, 250 mM CsF V underlie at least some actions of GTS-21 in vivo, it is also and 100 mM EGTA, pH 7.3 and had resistances of 0.5 to 2.0 M . Voltage electrodes were filled with 3 M KCl and had resistances of 1 conceivable that one or more metabolites of GTS-21 possesses to3MV. Because the general health of the oocytes, their ability to nicotinic agonist activity in humans. express the heterologous receptors and to maintain stable holding An initial pharmacokinetic study of GTS-21 in the rat potential were all correlated with the cell’s initial resting potential, indicated that only minor amounts of this compound were a criterion for minimal initial resting potential was set at 230 mV. excreted in an unaltered form (Mahnir et al., 1998). Both For analysis of concentration-responses relationships, oocytes were methoxy substituents on the benzylidene ring of GTS-21 placed in a Lucite recording chamber with a total volume of 0.6 ml were potential sites of primary hepatic metabolism by O- and were perfused at room temperature with frog Ringer’s (115 mM m demethylation (Kem et al., 1996). The principal human pri- NaCl, 2.5 mM KCl, 10 mM HEPES pH 7.3, 1.8 mM CaCl2) plus 1 M mary metabolite is 3-(4-hydroxy,2-methoxybenzylidene)- atropine to block potential muscarinic responses. The bath solution anabaseine, or 4OH-GTS-21 (Azuma et al., 1996). Because maintains calcium at a physiologically relevant concentration be- little is known about the properties of this metabolite relative cause extracellular calcium is an important modulator of neuronal nAChR function (Mulle et al., 1992, Vernino et al., 1992); calcium will to nicotinic receptors or their biological functions, we inves- also have indirect effects on agonist-evoked responses via calcium- tigated these properties in several systems. First, to deter- dependent chloride channels at this concentration. However, we Downloaded from mine whether 4OH-GTS-21 was an agonist or antagonist at have previously shown that calcium-dependent effects produce only human and rat nicotinic receptor subtypes, its effects were linear amplification of peak responses and do not distort the concen- measured on different AChR subunit combinations in the tration-responses relationships over a wide range of agonist concen- Xenopus oocyte system. Its binding to alpha-7 receptors was trations (Papke et al., 1997). characterized by displacement of high affinity a-BTX binding Drugs were diluted in perfusion solution and applied at a rate of 6 in human (SK-N-SH) and rat (PC12) cell lines. Finally, its ml/min for all concentrations and AChR subtypes. This represents jpet.aspetjournals.org biological activity was compared to GTS-21 relative to cyto- an agonist application protocol typical for oocyte-expression experi- protection against amyloid-induced toxicity in both cell lines. ments (Briggs et al., 1997; Luetje and Patrick, 1991; Papke and Heinemann, 1991; Papke et al., 1997). Responses were normalized An amyloid model for neurotoxicity was chosen because of its for the level of channel expression in each cell by measuring the sensitivity to nicotinic receptor-mediated cytoprotection response to an initial ACh application 5 min before presentation of (Kihara et al., 1997; Zamani et al., 1997) and its ability to the test concentration of ACh or experimental agonist. These control affect PC12 cells (Fagarasan and Efthimiopoulos, 1996); in ACh applications were: 1 mM ACh for muscle type AChRs; 10 mM addition to the well established involvement of amyloid-dep- ACh for a2b2, a3b2, and a4b2 AChRs; 30 mM for a3b4 AChRs and at ASPET Journals on August 8, 2016 osition in Alzheimer’s disease. Our results indicate that 300 mM ACh for a7 AChRs. Means and S.E.M. were calculated from 4OH-GTS-21 is an alpha-7-selective partial agonist with at the normalized responses of at least four oocytes for each experimen- least 10-fold greater efficacy for both human and rat a7 tal concentration. Comparisons of the GTS-21 and 4OH-GTS-21 AChRs than for any b-subunit containing AChR. It is also evoked responses of non-alpha-7 rodent AChRs were expressed rel- cytoprotective in human and rat cells, unlike GTS-21, which ative to ACh-evoked maximum responses.
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