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Molecular Pharmacology

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Research ArticleArticle

TTA-P2 Is a Potent and Selective Blocker of T-Type Calcium Channels in Rat Sensory Neurons and a Novel Antinociceptive Agent

WonJoo Choe, Richard B. Messinger, Emily Leach, Veit-Simon Eckle, Aleksandar Obradovic, Reza Salajegheh, Vesna Jevtovic-Todorovic and Slobodan M. Todorovic
Molecular Pharmacology November 2011, 80 (5) 900-910; DOI: https://doi.org/10.1124/mol.111.073205
WonJoo Choe
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Richard B. Messinger
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Emily Leach
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Veit-Simon Eckle
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Aleksandar Obradovic
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Reza Salajegheh
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Vesna Jevtovic-Todorovic
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Slobodan M. Todorovic
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Abstract

Several agents that are preferential T-type calcium (T-channel) blockers have shown promise as being effective in alleviating acute and chronic pain, suggesting an urgent need to identify even more selective and potent T-channel antagonists. We used small, acutely dissociated dorsal root ganglion (DRG) cells of adult rats to study the in vitro effects of 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2), a derivative of 4-aminomethyl-4-fluoropiperdine, on T currents, as well as other currents known to modulate pain transmission. We found that TTA-P2 potently and reversibly blocked DRG T currents with an IC50 of 100 nM and stabilized channel in the inactive state, whereas high-voltage-activated calcium and sodium currents were 100- to 1000-fold less sensitive to channel blocking effects. In in vivo studies, we found that intraperitoneal injections of 5 or 7.5 mg/kg TTA-P2 reduced pain responses in mice in phases 1 and 2 of the formalin test. Furthermore, TTA-P2, at 10 mg/kg i.p., selectively and completely reversed thermal hyperalgesia in diabetic rats treated with streptozocin but had no effect on the nociceptive response of healthy animals. The antihyperalgesic effects of TTA-P2 in diabetic rats were completely abolished by administration of oligonucleotide antisense for CaV3.2 isoform of T channels. Thus, TTA-P2 is not only the most potent and selective blocker of T channels in sensory neurons yet described, but it also demonstrates the potential for the pharmacological effectiveness of this approach in addressing altered nociceptive responses in animal models of both inflammatory and neuropathic pain.

Footnotes

  • This work was supported by The National Institutes of Health National Institute on Drug Abuse [Grant R21-DA029342]; the Harold Carron Endowment Fund; the American Diabetes Association [Basic Research Grant 7-09-BS-190]; the Department of Anesthesiology at the University of Virginia, InJe University; and a gift from Joseph C. Palumbo and Sandra C. Palumbo.

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

    doi:10.1124/mol.111.073205.

  • ABBREVIATIONS:

    HVA
    high-voltage-activated
    DRG
    dorsal root ganglion
    HEK
    human embryonic kidney
    PWL
    paw withdrawal latency
    STZ
    streptozocin
    TTX
    tetrodotoxin
    TTA-P2
    3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide)
    ECN
    [(3β, 5α, 17β)-17-hydroxyestrane-3-carbonitrile]
    CNS
    central nervous system
    P1
    phase 1
    P2
    phase 2
    AS
    antisense-CaV3.2
    MIS
    Mismatch-CaV3.2
    I-V
    current-voltage.

  • Received April 21, 2011.
  • Accepted August 5, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (5)
Molecular Pharmacology
Vol. 80, Issue 5
1 Nov 2011
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Research ArticleArticle

TTA-P2 Blocks T Currents in the Rat Sensory Neurons

WonJoo Choe, Richard B. Messinger, Emily Leach, Veit-Simon Eckle, Aleksandar Obradovic, Reza Salajegheh, Vesna Jevtovic-Todorovic and Slobodan M. Todorovic
Molecular Pharmacology November 1, 2011, 80 (5) 900-910; DOI: https://doi.org/10.1124/mol.111.073205

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Research ArticleArticle

TTA-P2 Blocks T Currents in the Rat Sensory Neurons

WonJoo Choe, Richard B. Messinger, Emily Leach, Veit-Simon Eckle, Aleksandar Obradovic, Reza Salajegheh, Vesna Jevtovic-Todorovic and Slobodan M. Todorovic
Molecular Pharmacology November 1, 2011, 80 (5) 900-910; DOI: https://doi.org/10.1124/mol.111.073205
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