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Research ArticleDrug Discovery and Translational Medicine

RG3487, a Novel Nicotinic α7 Receptor Partial Agonist, Improves Cognition and Sensorimotor Gating in Rodents

Tanya L. Wallace, Patrick M. Callahan, Ashok Tehim, Daniel Bertrand, Geoffrey Tombaugh, Shaojie Wang, Walter Xie, Wayne B. Rowe, Voon Ong, Elizabeth Graham, Alvin V. Terry Jr, Joshua S. Rodefer, Brian Herbert, Michael Murray, Richard Porter, Luca Santarelli and David A. Lowe
Journal of Pharmacology and Experimental Therapeutics January 2011, 336 (1) 242-253; DOI: https://doi.org/10.1124/jpet.110.171892
Tanya L. Wallace
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Patrick M. Callahan
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Ashok Tehim
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Daniel Bertrand
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Geoffrey Tombaugh
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Shaojie Wang
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Walter Xie
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Wayne B. Rowe
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Voon Ong
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Elizabeth Graham
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Alvin V. Terry Jr
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Joshua S. Rodefer
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Brian Herbert
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Michael Murray
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Richard Porter
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Luca Santarelli
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David A. Lowe
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Abstract

Neuronal nicotinic α7 acetylcholine receptors (α7nAChRs) are expressed primarily in the brain and are implicated in modulating many cognitive functions (e.g., attention, working and episodic memory). Not surprisingly, much effort has been committed to the development of molecules acting at α7nAChRs as potential therapies for a variety of central nervous system diseases (e.g., Alzheimer's). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride (RG3487) binds potently to the human α7nAChR (Ki = 6 nM), in which it acts as a partial agonist (63–69% of acetylcholine) as assessed by whole-cell patch-clamp recordings in both oocytes and QM7 cell lines. RG3487 activates human α7nAChRs with an EC50 of 0.8 μM (oocytes) and 7.7 μM (QM7 cells). RG3487 also exhibits antagonist properties at the serotonin 3 receptor [IC50 = 2.8 nM (oocytes), 32.7 nM (N1E-115 cells)]. In vivo, RG3487 improved object recognition memory in rats after acute [minimally effective dose (MED) 1.0 mg/kg p.o.] or repeated (10 day) administration at brain and plasma concentrations in the low-nanomolar range. Spatial learning deficits in age-impaired rats were reversed after RG3487 administration (MED: 0.03 mg/kg i.p.) as evaluated in the Morris water maze task. In the prepulse inhibition (PPI) of startle model of sensorimotor gating, RG3487 improved apomorphine-induced deficits in PPI performance (MED: 0.03 mg/kg i.p.) and reversed phencyclidine-induced impairments in an attentional set-shifting model of executive function (MED: ≤0.03 mg/kg i.p.). Cumulative evidence from these studies indicates RG3487 is a novel and potent α7nAChR partial agonist that improves cognitive performance and sensorimotor gating.

Footnotes

  • This work was supported by F. Hoffmann-La Roche, Ltd. and Memory Pharmaceuticals, Inc.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.171892.

  • ABBREVIATIONS:

    nAChR
    nicotinic acetylcholine receptor
    NOR
    novel object recognition
    MWM
    Morris water maze
    PPI
    prepulse inhibition
    MED
    minimally effective dose
    5-HT3
    serotonin 3
    5-HT3R
    5-HT3 receptor
    RG3487
    N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride
    PCP
    phencyclidine
    BSA
    bovine serum albumin
    FBS
    fetal bovine serum
    DMSO
    dimethyl sulfoxide
    diH20
    deionized water
    LMA
    locomotor activity
    GTS-21
    3(2,4-dimethoxybenzylidene)anabaseine
    SSR-180711
    (4-bromophenyl)1,4-diazabicyclo[3.2.2]nonane-4-carboxylate
    A-582941
    2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole
    MLA
    methyllycaconitine
    MDL72222
    tropanyl 3,5-dichlorobenzoate
    AI
    age impaired
    AU
    age unimpaired
    SD
    simple discrimination
    CD
    compound discrimination
    IDS
    intradimensional shift
    EDS
    extradimensional shift.

  • Received July 15, 2010.
  • Accepted October 18, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleDrug Discovery and Translational Medicine

RG3487, a Novel Nicotinic α7 Receptor Partial Agonist, Improves Cognition and Sensorimotor Gating in Rodents

Tanya L. Wallace, Patrick M. Callahan, Ashok Tehim, Daniel Bertrand, Geoffrey Tombaugh, Shaojie Wang, Walter Xie, Wayne B. Rowe, Voon Ong, Elizabeth Graham, Alvin V. Terry, Joshua S. Rodefer, Brian Herbert, Michael Murray, Richard Porter, Luca Santarelli and David A. Lowe
Journal of Pharmacology and Experimental Therapeutics January 1, 2011, 336 (1) 242-253; DOI: https://doi.org/10.1124/jpet.110.171892

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Research ArticleDrug Discovery and Translational Medicine

RG3487, a Novel Nicotinic α7 Receptor Partial Agonist, Improves Cognition and Sensorimotor Gating in Rodents

Tanya L. Wallace, Patrick M. Callahan, Ashok Tehim, Daniel Bertrand, Geoffrey Tombaugh, Shaojie Wang, Walter Xie, Wayne B. Rowe, Voon Ong, Elizabeth Graham, Alvin V. Terry, Joshua S. Rodefer, Brian Herbert, Michael Murray, Richard Porter, Luca Santarelli and David A. Lowe
Journal of Pharmacology and Experimental Therapeutics January 1, 2011, 336 (1) 242-253; DOI: https://doi.org/10.1124/jpet.110.171892
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