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Molecular Pharmacology

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Research ArticleOriginal Article

Kinetics of Penetration Influence the Apparent Potency of Vanilloids on TRPV1

Jozsef Lazar, Derek C. Braun, Attila Tóth, Yun Wang, Larry V. Pearce, Vladimir A. Pavlyukovets, Peter M. Blumberg, Susan H. Garfield, Stephen Wincovitch, Hyun-Kyung Choi and Jeewoo Lee
Molecular Pharmacology April 2006, 69 (4) 1166-1173; DOI: https://doi.org/10.1124/mol.105.019158
Jozsef Lazar
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Derek C. Braun
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Attila Tóth
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Yun Wang
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Larry V. Pearce
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Vladimir A. Pavlyukovets
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Peter M. Blumberg
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Susan H. Garfield
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Stephen Wincovitch
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Hyun-Kyung Choi
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Jeewoo Lee
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Abstract

Evidence that the ligand binding site of TRPV1 lies on the inner face of the plasma membrane and that much of the TRPV1 itself is localized to internal membranes suggests that the rate of ligand entry into the cell may be an important determinant of the kinetics of ligand action. In this study, we synthesized a BODIPY TR-labeled fluorescent capsaicin analog (CHK-884) so that we could directly measure ligand entry. We report that CHK-884 penetrated only slowly into Chinese hamster ovary (CHO) cells expressing rat TRPV1, with a t1/2 of 30 ± 4 min, and localized in the endoplasmic reticulum and Golgi. Although CHK-884 was only weakly potent for TRPV1 binding (Ki = 6400 ± 230 nM), it was appreciably more potent when assayed by intracellular calcium imaging and was 3.2-fold more potent with a 1-h incubation time (37 nM) than with a 5-min incubation time. Olvanil, a highly lipophilic vanilloid, yielded an EC50 of 4.3 nM upon intracellular calcium imaging with an incubation time of 1 h, compared with an EC50 value of 29.5 nM for calcium imaging assayed at 5 min. Likewise, the antagonist 5-iodo-resiniferatoxin (5-iodo-RTX) displayed a Ki of 4.2 pM if incubated with CHO-TRPV1 cells for 2 h before addition of capsaicin compared with 1.5 nM if added simultaneously. We conclude that some vanilloids may have slow kinetics of uptake; this slow uptake may affect assessment of structure activity relations and may represent a significant factor for vanilloid drug design.

  • Received September 21, 2005.
  • Accepted January 13, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 69 (4)
Molecular Pharmacology
Vol. 69, Issue 4
1 Apr 2006
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Research ArticleOriginal Article

Kinetics of Penetration Influence the Apparent Potency of Vanilloids on TRPV1

Jozsef Lazar, Derek C. Braun, Attila Tóth, Yun Wang, Larry V. Pearce, Vladimir A. Pavlyukovets, Peter M. Blumberg, Susan H. Garfield, Stephen Wincovitch, Hyun-Kyung Choi and Jeewoo Lee
Molecular Pharmacology April 1, 2006, 69 (4) 1166-1173; DOI: https://doi.org/10.1124/mol.105.019158

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Research ArticleOriginal Article

Kinetics of Penetration Influence the Apparent Potency of Vanilloids on TRPV1

Jozsef Lazar, Derek C. Braun, Attila Tóth, Yun Wang, Larry V. Pearce, Vladimir A. Pavlyukovets, Peter M. Blumberg, Susan H. Garfield, Stephen Wincovitch, Hyun-Kyung Choi and Jeewoo Lee
Molecular Pharmacology April 1, 2006, 69 (4) 1166-1173; DOI: https://doi.org/10.1124/mol.105.019158
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