Analgesic effects of a substituted N-triazole oxindole (TROX-1), a state-dependent, voltage-gated calcium channel 2 blocker.

Abstract

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.

• Authors: Catherine Abbadie, Owen B McManus, Shu-Yu Sun, Randal M Bugianesi, Ge Dai, Rodolfo J Haedo, James B Herrington, Gregory J Kaczorowski, McHardy M Smith, Andrew M Swensen, Vivien A Warren, Brande Williams, Stephen P Arneric, Cyrus Eduljee, Terrance P Snutch, Elizabeth W Tringham, Nina Jochnowitz, Annie Liang, D Euan MacIntyre, Erin McGowan, Shruti Mistry, Valerie V White, Scott B Hoyt, Clare London, Kathryn A Lyons, Patricia B Bunting, Sylvia Volksdorf, Joseph L Duffy
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 334 Issue 2 Pg. 545-55 (Aug 2010) ISSN: 1521-0103 [Electronic] United States
• PMID: 20439438 (Publication Type: Journal Article)

Chemical References

• 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
• Analgesics
• Cacna1b protein, mouse
• Cacna1b protein, rat
• Cacna1e protein, rat
• Calcium Channel Blockers
• Calcium Channels, N-Type
• Calcium Channels, R-Type
• Cation Transport Proteins
• Indoles
• Triazoles

Topics

• Analgesics (adverse effects, pharmacokinetics, pharmacology)
• Animals
• Baroreflex (drug effects)
• Biological Availability
• Calcium Channel Blockers (adverse effects, pharmacokinetics, pharmacology)
• Calcium Channels, N-Type (genetics, physiology)
• Calcium Channels, R-Type (physiology)
• Cation Transport Proteins (physiology)
• Cell Line
• Dogs
• Ganglia, Spinal (drug effects, physiology)
• Hyperalgesia (drug therapy)
• Hypotension, Orthostatic (chemically induced)
• Indoles (adverse effects, pharmacokinetics, pharmacology)
• Male
• Mice
• Mice, Knockout
• Neurons (drug effects, physiology)
• Pain (drug therapy, etiology)
• Patch-Clamp Techniques
• Rats
• Rats, Sprague-Dawley
• Triazoles (adverse effects, pharmacokinetics, pharmacology)