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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleDrug Discovery and Translational Medicine

Characterization of 2-[[4-Fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942), a Novel Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

Theo Dinklo, Hamdy Shaban, Jan Willem Thuring, Hilde Lavreysen, Karen E. Stevens, Lijun Zheng, Claire Mackie, Christopher Grantham, Ine Vandenberk, Greet Meulders, Luc Peeters, Hanne Verachtert, Erik De Prins and Anne S. J. Lesage
Journal of Pharmacology and Experimental Therapeutics February 2011, 336 (2) 560-574; DOI: https://doi.org/10.1124/jpet.110.173245
Theo Dinklo
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Hamdy Shaban
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Jan Willem Thuring
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Hilde Lavreysen
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Karen E. Stevens
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Lijun Zheng
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Claire Mackie
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Christopher Grantham
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Ine Vandenberk
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Greet Meulders
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Luc Peeters
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Hanne Verachtert
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Erik De Prins
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Anne S. J. Lesage
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Abstract

The α7 nicotinic acetylcholine receptor (nAChR) is a potential therapeutic target for the treatment of cognitive deficits associated with schizophrenia, Alzheimer's disease, Parkinson's disease, and attention-deficit/hyperactivity disorder. Activation of α7 nAChRs improved sensory gating and cognitive function in animal models and in early clinical trials. Here we describe the novel highly selective α7 nAChR positive allosteric modulator, 2-[[4-fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942). This compound enhances the choline-evoked rise in intracellular Ca2+ levels in the GH4C1 cell line expressing the cloned human α7 nAChR. JNJ-1930942 does not act on α4β2, α3β4 nAChRs or on the related 5-HT3A channel. Electrophysiological assessment in the GH4C1 cell line shows that JNJ-1930942 increases the peak and net charge response to choline, acetylcholine, and N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide (PNU-282987). The potentiation is obtained mainly by affecting the receptor desensitization characteristics, leaving activation and deactivation kinetics as well as recovery from desensitization relatively unchanged. Choline efficacy is increased over its full concentration response range, and choline potency is increased more than 10-fold. The potentiating effect is α7 channel-dependent, because it is blocked by the α7 antagonist methyllycaconitine. Moreover, in hippocampal slices, JNJ-1930942 enhances neurotransmission at hippocampal dentate gyrus synapses and facilitates the induction of long-term potentiation of electrically evoked synaptic responses in the dentate gyrus. In vivo, JNJ-1930942 reverses a genetically based auditory gating deficit in DBA/2 mice. JNJ-1930942 will be a useful tool to study the therapeutic potential of α7 nAChR potentiation in central nervous system disorders in which a deficit in α7 nAChR neurotransmission is hypothesized to be involved.

Footnotes

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

    doi:10.1124/jpet.110.173245.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    nAChR
    nicotinic acetylcholine receptor
    PAM
    positive allosteric modulator
    XY-4083
    N-(4-chlorophenyl)-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacetamide
    LY2087101
    [2-(4-fluoro-phenylamino)-4-methyl-thiazol-5-yl]-thiopen-3-yl-methanone
    NS-1738
    N-(5-chloro-2-hydroxyphenyl)-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea
    PNU-120596
    1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea
    TQS
    4-naphthalen-1-yl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonic acid amide
    A-867744
    4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide
    JNJ-1930942
    2-[[4-fluoro-3-(trifluoromethyl) phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol
    LTP
    long-term potentiation
    GH4C1α7
    GH4C1 cells stably transfected with the human α7 nAChR
    FCS
    fetal calf serum
    A-585539
    (1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane
    MLA
    methyllycaconitine
    DMSO
    dimethyl sulfoxide
    PBS
    phosphate-buffered saline
    ECS
    extracellular solution
    ACSF
    artificial cerebrospinal fluid
    fEPSP
    field excitatory postsynaptic potential
    MEA
    microelectrode array
    MPP
    medial perforant path
    DG
    dentate gyrus
    TBS
    θ-burst stimulation
    PVP
    polyvinylpyrrolidone
    α-BTX
    α-bungarotoxin
    PPR
    paired-pulse ratio
    CAMP
    the response amplitudes to the first (conditioning) stimulus S1
    TAMP
    the response amplitudes to the second (test) stimulus S2
    TC ratio
    TAMP/CAMP ratio
    GTS-21
    3-[(3E)-3-[(2,4-dimethoxyphenyl)methylidene]-5,6-dihydro-4H-pyridin-2-yl]pyridine.

  • Received August 20, 2010.
  • Accepted November 15, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 382 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 382, Issue 2
1 Aug 2022
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Characterization of 2-[[4-Fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942), a Novel Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor
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Research ArticleDrug Discovery and Translational Medicine

Characterization of 2-[[4-Fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942), a Novel Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

Theo Dinklo, Hamdy Shaban, Jan Willem Thuring, Hilde Lavreysen, Karen E. Stevens, Lijun Zheng, Claire Mackie, Christopher Grantham, Ine Vandenberk, Greet Meulders, Luc Peeters, Hanne Verachtert, Erik De Prins and Anne S. J. Lesage
Journal of Pharmacology and Experimental Therapeutics February 1, 2011, 336 (2) 560-574; DOI: https://doi.org/10.1124/jpet.110.173245

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Research ArticleDrug Discovery and Translational Medicine

Characterization of 2-[[4-Fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942), a Novel Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

Theo Dinklo, Hamdy Shaban, Jan Willem Thuring, Hilde Lavreysen, Karen E. Stevens, Lijun Zheng, Claire Mackie, Christopher Grantham, Ine Vandenberk, Greet Meulders, Luc Peeters, Hanne Verachtert, Erik De Prins and Anne S. J. Lesage
Journal of Pharmacology and Experimental Therapeutics February 1, 2011, 336 (2) 560-574; DOI: https://doi.org/10.1124/jpet.110.173245
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