Analgesic Effects of a Substituted N-Triazole Oxindole (TROX-1), a State-Dependent, Voltage-Gated Calcium Channel 2 Blocker

被引：82

作者：

Abbadie, Catherine ^{[2
]}

McManus, Owen B. ^{[3
]}

Sun, Shu-Yu ^{[2
]}

Bugianesi, Randal M. ^{[3
]}

Dai, Ge ^{[3
]}

Haedo, Rodolfo J. ^{[3
]}

Herrington, James B. ^{[3
]}

Kaczorowski, Gregory J. ^{[3
]}

Smith, McHardy M. ^{[3
]}

Swensen, Andrew M. ^{[3
]}

Warren, Vivien A. ^{[3
]}

Williams, Brande ^{[3
]}

Arneric, Stephen P. ^{[5
]}

Eduljee, Cyrus ^{[5
]}

Snutch, Terrance P. ^{[5
]}

Tringham, Elizabeth W. ^{[5
]}

Jochnowitz, Nina ^{[2
]}

Liang, Annie ^{[6
]}

MacIntyre, D. Euan ^{[2
]}

McGowan, Erin ^{[2
]}

Mistry, Shruti ^{[2
]}

White, Valerie V. ^{[2
]}

Hoyt, Scott B. ^{[1
]}

London, Clare ^{[1
]}

Lyons, Kathryn A. ^{[4
]}

Bunting, Patricia B. ^{[7
]}

Volksdorf, Sylvia ^{[7
]}

Duffy, Joseph L. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA

[2] Merck Res Labs, Dept Pharmacol, Rahway, NJ 07065 USA

[3] Merck Res Labs, Dept Ion Channel Res, Rahway, NJ 07065 USA

[4] Merck Res Labs, Dept Drug Metab, Rahway, NJ 07065 USA

[5] Neuromed Pharmaceut, Vancouver, BC, Canada

[6] Merck Res Labs, Dept Pain Res, West Point, PA USA

[7] Merck Res Labs, Dept Safety & Exploratory Pharmacol, West Point, PA USA

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2010年 / 334卷 / 02期

关键词：

CA-V; 2.2; ALPHA(1B) SUBUNIT; SYNAPTIC-TRANSMISSION; OMEGA-CONOPEPTIDES; NEUROPATHIC PAIN; MICE LACKING; P-TYPE; RAT; ATAXIA; ANTINOCICEPTION;

D O I：

10.1124/jpet.110.166363

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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-5ylmethyl)-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 (IC50 = 0.27 mu M) compared with hyperpolarized conditions (IC50 > 20 mu M). 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 con-ditions (IC50 = 0.4 mu M) than under hyperpolarized conditions (IC50 = 2.6 mu M), 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)2.2 channels in calcium imaging experiments in rat DRG neurons, indicating additional block of all Ca(v)2.2 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)2.2channel blocker may achieve a therapeutic window suitable for the treatment of chronic pain.

引用

页码：545 / 555

页数：11

共 41 条

[1] Splicing of α1A subunit gene generates phenotypic variants of P- and Q-type calcium channels [J].

Bourinet, E ;

Soong, TW ;

Sutton, K ;

Slaymaker, S ;

Mathews, E ;

Monteil, A ;

Zamponi, GW ;

Nargeot, J ;

Snutch, TP .

NATURE NEUROSCIENCE, 1999, 2 (05) :407-415

[2] CARDIOVASCULAR EFFECTS OF OMEGA-CONOPEPTIDES IN CONSCIOUS RATS - MECHANISMS OF ACTION [J].

BOWERSOX, SS ;

SINGH, T ;

NADASDI, L ;

ZUKOWSKAGROJEC, Z ;

VALENTINO, K ;

HOFFMAN, BB .

JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1992, 20 (05) :756-764

[3]

Bowersox SS, 1996, J PHARMACOL EXP THER, V279, P1243

[4] Voltage-gated calcium channels and pain [J].

Cao, Yu-Qing .

PAIN, 2006, 126 (1-3) :5-9

[5] QUANTITATIVE ASSESSMENT OF TACTILE ALLODYNIA IN THE RAT PAW [J].

CHAPLAN, SR ;

BACH, FW ;

POGREL, JW ;

CHUNG, JM ;

YAKSH, TL .

JOURNAL OF NEUROSCIENCE METHODS, 1994, 53 (01) :55-63

[6] Localization of N-type Ca2+ channels in the rat spinal cord following chronic constrictive nerve injury [J].

Cizkova, D ;

Marsala, J ;

Lukacova, N ;

Marsala, M ;

Jergova, S ;

Orendacova, J ;

Yaksh, TL .

EXPERIMENTAL BRAIN RESEARCH, 2002, 147 (04) :456-463

[7] EVIDENCE THAT ADJUVANT ARTHRITIS IN THE RAT IS ASSOCIATED WITH CHRONIC PAIN [J].

COLPAERT, FC .

PAIN, 1987, 28 (02) :201-222

[8] A high-throughput assay for evaluating state dependence and subtype selectivity of Cav2 calcium channel inhibitors [J].

Dai, Ge ;

Haedo, Rodolfo J. ;

Warren, Vivien A. ;

Ratliff, Kevin S. ;

Bugianesi, Randal M. ;

Rush, Alison ;

Williams, Mark E. ;

Herrington, James ;

Smith, McHardy M. ;

McManus, Owen B. ;

Swensen, Andrew M. .

ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES, 2008, 6 (02) :195-212

[9] Blockade of spinal N- and P-type, but not L-type, calcium channels inhibits the excitability of rat dorsal horn neurones produced by subcutaneous formalin inflammation [J].

Diaz, A ;

Dickenson, AH .

PAIN, 1997, 69 (1-2) :93-100

[10] Molecular pharmacology of high voltage-activated calcium channels [J].

Doering, CJ ;

Zamponi, GW .

JOURNAL OF BIOENERGETICS AND BIOMEMBRANES, 2003, 35 (06) :491-505

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