Analgesic Effects of a Substituted N-Triazole Oxindole (TROX-1), a State-Dependent, Voltage-Gated Calcium Channel 2 Blocker
| Autor: | James B Herrington, Brande S. Williams, Vivien A. Warren, Rodolfo Haedo, Annie Liang, Cyrus Eduljee, D. Euan MacIntyre, Terrance P. Snutch, Clare London, Randal M. Bugianesi, Shruti Mistry, Owen B. McManus, Gregory J. Kaczorowski, Scott B. Hoyt, McHardy M. Smith, Catherine Abbadie, Kathryn A. Lyons, Elizabeth Tringham, Ge Dai, Joseph L. Duffy, Patricia B. Bunting, Andrew M. Swensen, Sylvia Volksdorf, Valerie V. White, Stephen P. Arneric, Shu-Yu Sun, Nina Jochnowitz, Erin McGowan |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Indoles Patch-Clamp Techniques P-type calcium channel Biological Availability Pain chemistry.chemical_element Calcium Channels R-Type Pharmacology Calcium Cell Line Rats Sprague-Dawley Hypotension Orthostatic Mice Calcium Channels N-Type Dogs Calcium imaging Ganglia Spinal Animals Channel blocker Cation Transport Proteins Mice Knockout Neurons Analgesics TROX-1 Voltage-dependent calcium channel Chemistry Calcium channel T-type calcium channel Baroreflex Triazoles Calcium Channel Blockers Rats Hyperalgesia Molecular Medicine |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 334:545-555 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.110.166363 |
| Popis: | Voltage-gated calcium channel (Ca(v))2.2 (N-type calcium channels) are key components in nociceptive transmission pathways. Ziconotide, a state-independent peptide inhibitor of Ca(v)2.2 channels, is efficacious in treating refractory pain but exhibits a narrow therapeutic window and must be administered intrathecally. We have discovered an N-triazole oxindole, (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), as a small-molecule, state-dependent blocker of Ca(v)2 channels, and we investigated the therapeutic advantages of this compound for analgesia. TROX-1 preferentially inhibited potassium-triggered calcium influx through recombinant Ca(v)2.2 channels under depolarized conditions (IC(50) = 0.27 microM) compared with hyperpolarized conditions (IC(50)20 microM). In rat dorsal root ganglion (DRG) neurons, TROX-1 inhibited omega-conotoxin GVIA-sensitive calcium currents (Ca(v)2.2 channel currents), with greater potency under depolarized conditions (IC(50) = 0.4 microM) than under hyperpolarized conditions (IC(50) = 2.6 microM), indicating state-dependent Ca(v)2.2 channel block of native as well as recombinant channels. TROX-1 fully blocked calcium influx mediated by a mixture of Ca(v)2 channels in calcium imaging experiments in rat DRG neurons, indicating additional block of all Ca(v)2 family channels. TROX-1 reversed inflammatory-induced hyperalgesia with maximal effects equivalent to nonsteroidal anti-inflammatory drugs, and it reversed nerve injury-induced allodynia to the same extent as pregabalin and duloxetine. In contrast, no significant reversal of hyperalgesia was observed in Ca(v)2.2 gene-deleted mice. Mild impairment of motor function in the Rotarod test and cardiovascular functions were observed at 20- to 40-fold higher plasma concentrations than required for analgesic activities. TROX-1 demonstrates that an orally available state-dependent Ca(v)2 channel blocker may achieve a therapeutic window suitable for the treatment of chronic pain. |
| Databáze: | OpenAIRE |
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