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Molecular Pharmacology

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Research ArticleArticle

Characterization of the Substituted N-Triazole Oxindole TROX-1, a Small-Molecule, State-Dependent Inhibitor of Cav2 Calcium Channels

Andrew M. Swensen, James Herrington, Randal M. Bugianesi, Ge Dai, Rodolfo J. Haedo, Kevin S. Ratliff, McHardy M. Smith, Vivien A. Warren, Stephen P. Arneric, Cyrus Eduljee, David Parker, Terrance P. Snutch, Scott B. Hoyt, Clare London, Joseph L. Duffy, Gregory J. Kaczorowski and Owen B. McManus
Molecular Pharmacology March 2012, 81 (3) 488-497; DOI: https://doi.org/10.1124/mol.111.075226
Andrew M. Swensen
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James Herrington
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Randal M. Bugianesi
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Ge Dai
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Rodolfo J. Haedo
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Kevin S. Ratliff
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McHardy M. Smith
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Vivien A. Warren
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Stephen P. Arneric
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Cyrus Eduljee
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David Parker
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Terrance P. Snutch
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Scott B. Hoyt
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Clare London
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Joseph L. Duffy
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Gregory J. Kaczorowski
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Owen B. McManus
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Abstract

Biological, genetic, and clinical evidence provide validation for N-type calcium channels (CaV2.2) as therapeutic targets for chronic pain. A state-dependent CaV2.2 inhibitor may provide an improved therapeutic window over ziconotide, the peptidyl CaV2.2 inhibitor used clinically. Supporting this notion, we recently reported that in preclinical models, the state-dependent CaV2 inhibitor (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1) has an improved therapeutic window compared with ziconotide. Here we characterize TROX-1 inhibition of Cav2.2 channels in more detail. When channels are biased toward open/inactivated states by depolarizing the membrane potential under voltage-clamp electrophysiology, TROX-1 inhibits CaV2.2 channels with an IC50 of 0.11 μM. The voltage dependence of CaV2.2 inhibition was examined using automated electrophysiology. TROX-1 IC50 values were 4.2, 0.90, and 0.36 μM at −110, −90, and −70 mV, respectively. TROX-1 displayed use-dependent inhibition of CaV2.2 with a 10-fold IC50 separation between first (27 μM) and last (2.7 μM) pulses in a train. In a fluorescence-based calcium influx assay, TROX-1 inhibited CaV2.2 channels with an IC50 of 9.5 μM under hyperpolarized conditions and 0.69 μM under depolarized conditions. Finally, TROX-1 potency was examined across the CaV2 subfamily. Depolarized IC50 values were 0.29, 0.19, and 0.28 μM by manual electrophysiology using matched conditions and 1.8, 0.69, and 1.1 μM by calcium influx for CaV2.1, CaV2.2, and CaV2.3, respectively. Together, these in vitro data support the idea that a state-dependent, non–subtype-selective CaV2 channel inhibitor can achieve an improved therapeutic window over the relatively state-independent CaV2.2-selective inhibitor ziconotide in preclinical models of chronic pain.

Footnotes

  • A.M.S., J.H., R.M.B., G.D., R.J.H., K.S.R., M.M.S., V.A.W., S.B.H., C.L., J.L.D., G.J.K., and O.B.M. are present or former employees of Merck Research Laboratories and may hold stock or stock options in Merck and Co. S.P.A., C.E., D.P., and T.P.S. are present or former employees in Zalicus Pharmaceuticals and may hold stock or stock options in Zalicus Pharmaceuticals.

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

    http://dx.doi.org/10.1124/mol.111.075226.

  • ABBREVIATIONS:

    Cav
    voltage-gated calcium channel
    DMSO
    dimethyl sulfoxide
    HEK
    human embryonic kidney
    FLIPR
    fluorometric imaging plate reader
    TROX-1
    (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one.

  • Received August 10, 2011.
  • Accepted December 21, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Research ArticleArticle

Characterization of TROX-1, A State-Dependent CaV2 Inhibitor

Andrew M. Swensen, James Herrington, Randal M. Bugianesi, Ge Dai, Rodolfo J. Haedo, Kevin S. Ratliff, McHardy M. Smith, Vivien A. Warren, Stephen P. Arneric, Cyrus Eduljee, David Parker, Terrance P. Snutch, Scott B. Hoyt, Clare London, Joseph L. Duffy, Gregory J. Kaczorowski and Owen B. McManus
Molecular Pharmacology March 1, 2012, 81 (3) 488-497; DOI: https://doi.org/10.1124/mol.111.075226

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Research ArticleArticle

Characterization of TROX-1, A State-Dependent CaV2 Inhibitor

Andrew M. Swensen, James Herrington, Randal M. Bugianesi, Ge Dai, Rodolfo J. Haedo, Kevin S. Ratliff, McHardy M. Smith, Vivien A. Warren, Stephen P. Arneric, Cyrus Eduljee, David Parker, Terrance P. Snutch, Scott B. Hoyt, Clare London, Joseph L. Duffy, Gregory J. Kaczorowski and Owen B. McManus
Molecular Pharmacology March 1, 2012, 81 (3) 488-497; DOI: https://doi.org/10.1124/mol.111.075226
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