Presentation Abstract

Program#/Poster#: 227.1/B122
Title: In vitro pharmacological characterization of a novel selective α7 neuronal nicotinic acetylcholine receptor agonist ABT-107
Location: South Hall A
Presentation Time: Sunday, Oct 18, 2009, 1:00 PM - 2:00 PM
Authors: *J. MALYSZ1, D. J. ANDERSON1, J. H. GRØNLIEN1, J. JI1, W. H. BUNNELLE1, M. HÅKERUD1, K. THORIN-HAGENE1, H. WEEN1, R. HELFRICH1, C. A. BRIGGS1, M. D. MEYER1, T. DYHRING2, P. K. AHRING2, E. Ø. NIELSEN2, D. PETERS2, D. B. TIMMERMANN2, M. GOPALAKRISHNAN1;
1Abbott, Abbott Park, IL; 2NeuroSearch, Ballerup, Denmark
Abstract: α7 neuronal nicotinic acetylcholine receptors (nAChRs) are distributed in the CNS including cortex and hippocampus, regions involved in cognitive processes. Enhancement of α7 nAChR activity is considered as a viable therapeutic target for ameliorating cognitive deficits present in Alzheimer’s disease and schizophrenia and potentially to provide neuroprotection. In this study, we describe the in vitro profile of a novel selective α7 nAChR agonist, ABT-107, using radioligand binding, neurotransmitter uptake, electrophysiology, and Ca2+ imaging methodologies. ABT-107 displayed comparable high affinity binding to cortical membranes from rat (Ki = 0.2 nM) and human (Ki = 0.6 nM) using [3H]A-585,539. The affinities for other nAChRs examined were at least 550-fold lower, at rat α4β2* (Ki = 4 μM, cortex, [3H]cytisine) and human α1β1γδ (Ki = 15 μM, TE671, [3H] α-bungarotoxin), and for other receptors, weak or negligible (Ki at least 3 μM). ABT-107 did not inhibit uptake of either [3H]DA or [3H]NE (IC50 > 100 μM) and only weakly of [3H]5-HT (IC50 = 1.7 μM) in rat brain. ABT-107 exhibited similar potency and efficacy activating human and rat α7 nAChRs expressed in X. oocytes (EC50 ~ 0.3 μM, 76 - 79%), examined by TEVC. In rat CA1 hippocampus interneurons, the application of ABT-107 (300 nM in puff pipette) evoked α7-like currents, which were inhibited by MLA (10 nM). ABT-107 did not evoke any detectible current in X. oocytes expressing human α3β4 (EC50 > 300 μM), chimeric (α6α3)β4 (EC50 > 300 μM), or 5-HT3A receptors (EC50> 30 μM also negligible antagonism, IC50 > 30 μM). Similarly in Ca2+ imaging experiments, ABT-107 did not evoke any signals in IMR-32 cells, expressing human α3β4*, or at human α4β2 expressed in HEK-293 cells (EC50 > 100 μM) and only weak effect at human α4β4 expressed in HEK-293 cells (EC50 = 3 μM, 12%). In summary, ABT-107 exhibits high affinity, selectivity, and favorable agonism profile at the α7 nAChR suitable for characterizing the roles of this subtype in both in vitro and in vivo studies.
Disclosures:   J. Malysz, Abbott, A. Employment (full or part-time); D.J. Anderson, Abbott, A. Employment (full or part-time); J.H. Grønlien, Abbott, A. Employment (full or part-time); J. Ji, Abbott, A. Employment (full or part-time); W.H. Bunnelle, Abbott, A. Employment (full or part-time); M. Håkerud, Abbott, A. Employment (full or part-time); K. Thorin-Hagene, Abbott, A. Employment (full or part-time); H. Ween, Abbott, A. Employment (full or part-time); R. Helfrich, Abbott, A. Employment (full or part-time); C.A. Briggs, Abbott, A. Employment (full or part-time); M.D. Meyer, Abbott, A. Employment (full or part-time); T. Dyhring, NeuroSearch, A. Employment (full or part-time); P.K. Ahring, NeuroSearch, A. Employment (full or part-time); E.Ø. Nielsen, NeuroSearch, A. Employment (full or part-time); D. Peters, NeuroSearch, A. Employment (full or part-time); D.B. Timmermann, NeuroSearch, A. Employment (full or part-time); M. Gopalakrishnan, Abbott, A. Employment (full or part-time).
Keyword(s): NICOTINIC RECEPTOR
ACETYLCHOLINE RECEPTOR
IN VITRO
Support: Abbott
[Authors]. [Abstract Title]. Program No. XXX.XX. 2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009. Online.

2009 Copyright by the Society for Neuroscience all rights reserved. Permission to republish any abstract or part of any abstract in any form must be obtained in writing by SfN office prior to publication.




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