Recent progress in the discovery and development of N-type calcium channel modulators for the treatment of pain

Progress in Medicinal Chemistry

Volumn 53, Issue , 2014, Pages 147-186

  Lee, Margaret S ^a  

^a Zalicus Inc   (United States)

Author keywords

CACNA1B; Inactivation; N type calcium channel; Pain; State dependent; Use dependent; Voltage gated calcium channel; Conotoxin

Indexed keywords

CALCIUM CHANNEL BLOCKING AGENT; CALCIUM CHANNEL N TYPE; CALCIUM CHANNEL N TYPE MODULATOR; CALCIUM CHANNEL STIMULATING AGENT; CNV 2197944; INDOLE DERIVATIVE; OXINDOLE; PEPTIDE; PEPTIDOMIMETIC AGENT; PIPERAZINE; PIPERIDINE; SMALL MOLECULE TRANSPORT AGENT; UNCLASSIFIED DRUG; VENOM; VOLTAGE GATED CALCIUM CHANNEL; Z 160; PIPERAZINE DERIVATIVE; PIPERIDINE DERIVATIVE;

BIOMIMETICS; DRUG RESEARCH; HUMAN; MOLECULE; NONHUMAN; PAIN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN FUNCTION; PROTEIN STRUCTURE; REVIEW; SIGNAL TRANSDUCTION; TREATMENT OUTCOME; AMINO ACID SEQUENCE; ANIMAL; DRUG DEVELOPMENT; DRUG EFFECTS; MOLECULAR GENETICS; PHYSIOLOGY;

AMINO ACID SEQUENCE; ANIMALS; CALCIUM CHANNELS, N-TYPE; DRUG DISCOVERY; HUMANS; INDOLES; MOLECULAR SEQUENCE DATA; PAIN; PEPTIDES; PIPERAZINES; PIPERIDINES;

EID: 84892422212     PISSN: 00796468     EISSN: 18757863     Source Type: Book Series    
DOI: 10.1016/B978-0-444-63380-4.00004-4     Document Type: Chapter

References (153)

1. D.J. Triggle Calcium channel antagonists: clinical uses - past, present and future Biochem Pharmacol 74 1 2007 1 9
2. C.G. Mohan, and T. Gandhi Therapeutic potential of voltage gated calcium channels Mini Rev Med Chem 8 12 2008 1285 1290
3. J.P. Bingham, E. Mitsunaga, and Z.L. Bergeron Drugs from slugs - past, present and future perspectives of omega-conotoxin research Chem Biol Interact 183 1 2010 1 18
4. S. Vink, and P.F. Alewood Targeting voltage-gated calcium channels: developments in peptide and small-molecule inhibitors for the treatment of neuropathic pain Br J Pharmacol 167 5 2012 970 989
5. L.A. Swayne, and E. Bourinet Voltage-gated calcium channels in chronic pain: emerging role of alternative splicing Pflugers Arch 456 3 2008 459 466
6. E. Loots, and E.Y. Isacoff Molecular coupling of S4 to a K(+) channel's slow inactivation gate J Gen Physiol 116 5 2000 623 636
7. F. Bezanilla Voltage sensor movements J Gen Physiol 120 4 2002 465 473
8. S.R. Sousa, I. Vetter, and R.J. Lewis Venom peptides as a rich source of cav2.2 channel blockers Toxins (Basel) 5 2 2013 286 314
9. Z. Buraei, and J. Yang Structure and function of the beta subunit of voltage-gated Ca(2)(+) channels Biochim Biophys Acta 1828 7 2013 1530 1540
10. M. Pragnell, M. De Waard, Y. Mori, T. Tanabe, T.P. Snutch, and K.P. Campbell Calcium channel beta-subunit binds to a conserved motif in the I-II cytoplasmic linker of the alpha 1-subunit Nature 368 6466 1994 67 70
11. M. De Waard, D.R. Witcher, M. Pragnell, H. Liu, and K.P. Campbell Properties of the alpha 1-beta anchoring site in voltage-dependent Ca2 + channels J Biol Chem 270 20 1995 12056 12064
12. D.R. Witcher, M. De Waard, H. Liu, M. Pragnell, and K.P. Campbell Association of native Ca2 + channel beta subunits with the alpha 1 subunit interaction domain J Biol Chem 270 30 1995 18088 18093
13. Z. Buraei, and J. Yang The β subunit of voltage-gated Ca2 + channels Physiol Rev 90 4 2010 1461 1506
14. N. Klugbauer, L. Lacinova, E. Marais, M. Hobom, and F. Hofmann Molecular diversity of the calcium channel alpha2delta subunit J Neurosci 19 2 1999 684 691
15. N. Qin, S. Yagel, M.L. Momplaisir, E.E. Codd, and M.R. D'Andrea Molecular cloning and characterization of the human voltage-gated calcium channel alpha(2)delta-4 subunit Mol Pharmacol 62 3 2002 485 496
16. A. Davies, I. Kadurin, A. Alvarez-Laviada, L. Douglas, M. Nieto-Rostro, and C.S. Bauer et al. The alpha2delta subunits of voltage-gated calcium channels form GPI-anchored proteins, a posttranslational modification essential for function Proc Natl Acad Sci U S A 107 4 2010 1654 1659
17. W.A. Catterall Voltage-gated calcium channels Cold Spring Harb Perspect Biol 3 8 2011 a003947
18. Z.D. Luo, N.A. Calcutt, E.S. Higuera, C.R. Valder, Y.H. Song, and C.I. Svensson et al. Injury type-specific calcium channel alpha 2 delta-1 subunit up-regulation in rat neuropathic pain models correlates with antiallodynic effects of gabapentin J Pharmacol Exp Ther 303 3 2002 1199 1205
19. N.B. Finnerup, S.H. Sindrup, and T.S. Jensen Chronic neuropathic pain: mechanisms, drug targets and measurement Fundam Clin Pharmacol 21 2 2007 129 136
20. J. Hendrich, A.T. Van Minh, F. Heblich, M. Nieto-Rostro, K. Watschinger, and J. Striessnig et al. Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin Proc Natl Acad Sci U S A 105 9 2008 3628 3633
21. A. Davies, J. Hendrich, A.T. Van Minh, J. Wratten, L. Douglas, and A.C. Dolphin Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels Trends Pharmacol Sci 28 5 2007 220 228
22. A.C. Dolphin Calcium channel α2δ subunits in epilepsy and as targets for antiepileptic drugs J.L. Noebels, M. Avoli, M. Rogawski, R. Olsen, A. Delgado-Escueta, Jasper's basic mechanisms epilepsies 2012 Oxford University Press Bethesda, MD
23. V.A. Letts, R. Felix, G.H. Biddlecome, J. Arikkath, C.L. Mahaffey, and A. Valenzuela et al. The mouse stargazer gene encodes a neuronal Ca2 + -channel gamma subunit Nat Genet 19 4 1998 340 347
24. D.L. Minor Jr., and F. Findeisen Progress in the structural understanding of voltage-gated calcium channel (CaV) function and modulation Channels (Austin) 4 6 2010 459 474
25. I. Calin-Jageman, and A. Lee Ca(v)1 L-type Ca2 + channel signaling complexes in neurons J Neurochem 105 3 2008 573 583
26. W.A. Catterall, and A.P. Few Calcium channel regulation and presynaptic plasticity Neuron 59 6 2008 882 901
27. W.A. Catterall, E. Perez-Reyes, T.P. Snutch, and J. Striessnig International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels Pharmacol Rev 57 4 2005 411 425
28. H.W. Tedford, and G.W. Zamponi Direct G protein modulation of Cav2 calcium channels Pharmacol Rev 58 4 2006 837 862
29. E. Tringham, and T.P. Snutch Volgate-gated N-type and T-type calcium channels and excitability disorders V.K. Gribkoff, L.K. Kaczmarek, Structure, function and modulation of neuronal voltage-gated Ion channels 2008 John Wiley & Sons, Inc. Hoboken, NJ
30. S. Hering, S. Berjukow, S. Sokolov, R. Marksteiner, R.G. Weiss, and R. Kraus et al. Molecular determinants of inactivation in voltage-gated Ca2 + channels J Physiol 528 Pt 2 2000 237 249
31. S.C. Stotz, S.E. Jarvis, and G.W. Zamponi Functional roles of cytoplasmic loops and pore lining transmembrane helices in the voltage-dependent inactivation of HVA calcium channels J Physiol 554 Pt 2 2004 263 273
32. L. Lacinova, N. Klugbauer, and F. Hofmann State- and isoform-dependent interaction of isradipine with the alpha1C L-type calcium channel Pflugers Arch 440 1 2000 50 60
33. B.P. Bean Nitrendipine block of cardiac calcium channels: high-affinity binding to the inactivated state Proc Natl Acad Sci U S A 81 20 1984 6388 6392
34. B.Z. Peterson, and W.A. Catterall Allosteric interactions required for high-affinity binding of dihydropyridine antagonists to Ca(V)1.1 channels are modulated by calcium in the pore Mol Pharmacol 70 2 2006 667 675
35. I. Niespodziany, N. Leclere, C. Vandenplas, P. Foerch, and C. Wolff Comparative study of lacosamide and classical sodium channel blocking antiepileptic drugs on sodium channel slow inactivation J Neurosci Res 91 3 2013 436 443
36. R.J. Winquist, J.Q. Pan, and V.K. Gribkoff Use-dependent blockade of Cav2.2 voltage-gated calcium channels for neuropathic pain Biochem Pharmacol 70 4 2005 489 499
37. M.C. Nowycky, A.P. Fox, and R.W. Tsien Three types of neuronal calcium channel with different calcium agonist sensitivity Nature 316 6027 1985 440 443
38. B.M. Olivera, G.P. Miljanich, J. Ramachandran, and M.E. Adams Calcium channel diversity and neurotransmitter release: the omega-conotoxins and omega-agatoxins Annu Rev Biochem 63 1994 823 867
39. J.C. Poncer, R.A. McKinney, B.H. Gahwiler, and S.M. Thompson Either N- or P-type calcium channels mediate GABA release at distinct hippocampal inhibitory synapses Neuron 18 3 1997 463 472
40. A.B. Ali, and C. Nelson Distinct Ca2 + channels mediate transmitter release at excitatory synapses displaying different dynamic properties in rat neocortex Cereb Cortex 16 3 2006 386 393
41. W. Li, C. Thaler, and P. Brehm Calcium channels in Xenopus spinal neurons differ in somas and presynaptic terminals J Neurophysiol 86 1 2001 269 279
42. E.F. Stanley Single calcium channels and acetylcholine release at a presynaptic nerve terminal Neuron 11 6 1993 1007 1011
43. J. Sheng, L. He, H. Zheng, L. Xue, F. Luo, and W. Shin et al. Calcium-channel number critically influences synaptic strength and plasticity at the active zone Nat Neurosci 15 7 2012 998 1006
44. D. Cizkova, J. Marsala, N. Lukacova, M. Marsala, S. Jergova, and J. Orendacova et al. Localization of N-type Ca2 + channels in the rat spinal cord following chronic constrictive nerve injury Exp Brain Res 147 4 2002 456 463
45. L.M. Smyth, I.A. Yamboliev, and V.N. Mutafova-Yambolieva N-type and P/Q-type calcium channels regulate differentially the release of noradrenaline, ATP and beta-NAD in blood vessels Neuropharmacology 56 2 2009 368 378
46. D. Pruneau, and J.A. Angus Omega-conotoxin GVIA is a potent inhibitor of sympathetic neurogenic responses in rat small mesenteric arteries Br J Pharmacol 100 1 1990 180 184
47. Y. Lin, S.I. McDonough, and D. Lipscombe Alternative splicing in the voltage-sensing region of N-Type CaV2.2 channels modulates channel kinetics J Neurophysiol 92 5 2004 2820 2830
48. A.C. Dolphin Beta subunits of voltage-gated calcium channels J Bioenerg Biomembr 35 6 2003 599 620
49. P.G. Patil, D.L. Brody, and D.T. Yue Preferential closed-state inactivation of neuronal calcium channels Neuron 20 5 1998 1027 1038
50. L.P. Jones, C.D. DeMaria, and D.T. Yue N-type calcium channel inactivation probed by gating-current analysis Biophys J 76 5 1999 2530 2552
51. C. Kim, K. Jun, T. Lee, S.S. Kim, M.W. McEnery, and H. Chin et al. Altered nociceptive response in mice deficient in the alpha(1B) subunit of the voltage-dependent calcium channel Mol Cell Neurosci 18 2 2001 235 245
52. H. Saegusa, T. Kurihara, S. Zong, A. Kazuno, Y. Matsuda, and T. Nonaka et al. Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca2 + channel EMBO J 20 10 2001 2349 2356
53. H. Saegusa, Y. Matsuda, and T. Tanabe Effects of ablation of N- and R-type Ca(2 +) channels on pain transmission Neurosci Res 43 1 2002 1 7
54. M. Ino, T. Yoshinaga, M. Wakamori, N. Miyamoto, E. Takahashi, and J. Sonoda et al. Functional disorders of the sympathetic nervous system in mice lacking the alpha 1B subunit (Cav 2.2) of N-type calcium channels Proc Natl Acad Sci U S A 98 9 2001 5323 5328
55. D. Pietrobon Function and dysfunction of synaptic calcium channels: insights from mouse models Curr Opin Neurobiol 15 3 2005 257 265
56. W.G. Brose, D.P. Gutlove, R.R. Luther, S.S. Bowersox, and D. McGuire Use of intrathecal SNX-111, a novel, N-type, voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain Clin J Pain 13 3 1997 256 259
57. P.S. Staats, T. Yearwood, S.G. Charapata, R.W. Presley, M.S. Wallace, and M. Byas-Smith et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial JAMA 291 1 2004 63 70
58. M.S. Wallace Ziconotide: a new nonopioid intrathecal analgesic for the treatment of chronic pain Expert Rev Neurother 6 10 2006 1423 1428
59. D.J. Adams, and G. Berecki Mechanisms of conotoxin inhibition of N-type (Ca(v)2.2) calcium channels Biochim Biophys Acta 1828 7 2013 1619 1628
60. D.J. Adams, B. Callaghan, and G. Berecki Analgesic conotoxins: block and G protein-coupled receptor modulation of N-type (Ca(V) 2.2) calcium channels Br J Pharmacol 166 2 2012 486 500
61. R.J. Lewis, S. Dutertre, I. Vetter, and M.J. Christie Conus venom peptide pharmacology Pharmacol Rev 64 2 2012 259 298
62. R.A. Atkinson, B. Kieffer, A. Dejaegere, F. Sirockin, and J.F. Lefevre Structural and dynamic characterization of omega-conotoxin MVIIA: the binding loop exhibits slow conformational exchange Biochemistry 39 14 2000 3908 3919
63. M.E. Adams, R.A. Myers, J.S. Imperial, and B.M. Olivera Toxityping rat brain calcium channels with omega-toxins from spider and cone snail venoms Biochemistry 32 47 1993 12566 12570
64. K. Dunlap, J.I. Luebke, and T.J. Turner Identification of calcium channels that control neurosecretion Science 266 5186 1994 828 831
65. R.J. Lewis, K.J. Nielsen, D.J. Craik, M.L. Loughnan, D.A. Adams, and I.A. Sharpe et al. Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes J Biol Chem 275 45 2000 35335 35344
66. P.T. Ellinor, J.F. Zhang, W.A. Horne, and R.W. Tsien Structural determinants of the blockade of N-type calcium channels by a peptide neurotoxin Nature 372 6503 1994 272 275
67. J. Payandeh, T. Scheuer, N. Zheng, and W.A. Catterall The crystal structure of a voltage-gated sodium channel Nature 475 7356 2011 353 358
68. J.I. Kim, M. Takahashi, A. Ogura, T. Kohno, Y. Kudo, and K. Sato Hydroxyl group of Tyr13 is essential for the activity of omega-conotoxin GVIA, a peptide toxin for N-type calcium channel J Biol Chem 269 39 1994 23876 23878
69. M.J. Lew, J.P. Flinn, P.K. Pallaghy, R. Murphy, S.L. Whorlow, and C.E. Wright et al. Structure-function relationships of omega-conotoxin GVIA. Synthesis, structure, calcium channel binding, and functional assay of alanine-substituted analogues J Biol Chem 272 18 1997 12014 12023
70. K.J. Nielsen, D. Adams, L. Thomas, T. Bond, P.F. Alewood, and D.J. Craik et al. Structure-activity relationships of omega-conotoxins MVIIA, MVIIC and 14 loop splice hybrids at N and P/Q-type calcium channels J Mol Biol 289 5 1999 1405 1421
71. G. Berecki, L. Motin, A. Haythornthwaite, S. Vink, P. Bansal, and R. Drinkwater et al. Analgesic (omega)-conotoxins CVIE and CVIF selectively and voltage-dependently block recombinant and native N-type calcium channels Mol Pharmacol 77 2 2010 139 148
72. J. Mould, T. Yasuda, C.I. Schroeder, A.M. Beedle, C.J. Doering, and G.W. Zamponi et al. The alpha2delta auxiliary subunit reduces affinity of omega-conotoxins for recombinant N-type (Cav2.2) calcium channels J Biol Chem 279 33 2004 34705 34714
73. L. Motin, T. Yasuda, C.I. Schroeder, R.J. Lewis, and D.J. Adams Omega-conotoxin CVIB differentially inhibits native and recombinant N- and P/Q-type calcium channels Eur J Neurosci 25 2 2007 435 444
74. L. Motin, and D.J. Adams omega-Conotoxin inhibition of excitatory synaptic transmission evoked by dorsal root stimulation in rat superficial dorsal horn Neuropharmacology 55 5 2008 860 864
75. V. Herzig, D.L. Wood, F. Newell, P.A. Chaumeil, Q. Kaas, and G.J. Binford et al. ArachnoServer 2.0, an updated online resource for spider toxin sequences and structures Nucleic Acids Res 39 Database issue 2011 D653 D657
76. Z. Liu, J. Dai, L. Dai, M. Deng, Z. Hu, and W. Hu et al. Function and solution structure of Huwentoxin-X, a specific blocker of N-type calcium channels, from the Chinese bird spider Ornithoctonus huwena J Biol Chem 281 13 2006 8628 8635
77. K. Peng, X.D. Chen, and S.P. Liang The effect of Huwentoxin-I on Ca(2 +) channels in differentiated NG108-15 cells, a patch-clamp study Toxicon 39 4 2001 491 498
78. J.G. McGivern Ziconotide: a review of its pharmacology and use in the treatment of pain Neuropsychiatr Dis Treat 3 1 2007 69 85
79. L.R. Webster, R. Fisher, S. Charapata, and M.S. Wallace Long-term intrathecal ziconotide for chronic pain: an open-label study J Pain Symptom Manage 37 3 2009 363 372
80. M.S. Wallace, P.S. Kosek, P. Staats, R. Fisher, D.M. Schultz, and M. Leong Phase II, open-label, multicenter study of combined intrathecal morphine and ziconotide: addition of ziconotide in patients receiving intrathecal morphine for severe chronic pain Pain Med 9 3 2008 271 281
81. M.S. Wallace, R.L. Rauck, and T. Deer Ziconotide combination intrathecal therapy: rationale and evidence Clin J Pain 26 7 2010 635 644
82. Prialt. Package insert.
83. C.E. Wright, A.D. Robertson, S.L. Whorlow, and J.A. Angus Cardiovascular and autonomic effects of omega-conotoxins MVIIA and CVID in conscious rabbits and isolated tissue assays Br J Pharmacol 131 7 2000 1325 1336
84. D. McGuire, S. Bowersox, J.D. Fellmann, and R.R. Luther Sympatholysis after neuron-specific, N-type, voltage-sensitive calcium channel blockade: first demonstration of N-channel function in humans J Cardiovasc Pharmacol 30 3 1997 400 403
85. J.G. McGivern Targeting N-type and T-type calcium channels for the treatment of pain Drug Discov Today 11 5-6 2006 245 253
86. R.D. Penn, and J.A. Paice Adverse effects associated with the intrathecal administration of ziconotide Pain 85 1-2 2000 291 296
87. A. Takahara, H. Koganei, T. Takeda, and S. Iwata Antisympathetic and hemodynamic property of a dual L/N-type Ca(2 +) channel blocker cilnidipine in rats Eur J Pharmacol 434 1-2 2002 43 47
88. T. Yamamoto, and A. Takahara Recent updates of N-type calcium channel blockers with therapeutic potential for neuropathic pain and stroke Curr Top Med Chem 9 4 2009 377 395
89. M.T. Smith, P.J. Cabot, F.B. Ross, A.D. Robertson, and R.J. Lewis The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices Pain 96 1-2 2002 119 127
90. A. Kolosov, L. Aurini, E.D. Williams, I. Cooke, and C.S. Goodchild Intravenous injection of leconotide, an omega conotoxin: synergistic antihyperalgesic effects with morphine in a rat model of bone cancer pain Pain Med 12 6 2011 923 941
91. A. Kolosov, C.S. Goodchild, and I. Cooke CNSB004 (Leconotide) causes antihyperalgesia without side effects when given intravenously: a comparison with ziconotide in a rat model of diabetic neuropathic pain Pain Med 11 2 2010 262 273
92. Pharmaceuticals R. http://wwwrelevarepharmacom/, accessed September 2013.
93. Gomes M, Maximo Prado M, Prado VF. PHA1B toxin, cDNA of PHA1B toxin gene, pharmaceutical composition containing PHA1B toxin, process and product. US Patent Application 2010; US20100168009.
94. A.H. Souza, J. Ferreira, N. Cordeiro Mdo, L.B. Vieira, C.J. De Castro, and G. Trevisan et al. Analgesic effect in rodents of native and recombinant Ph alpha 1beta toxin, a high-voltage-activated calcium channel blocker isolated from armed spider venom Pain 140 1 2008 115 126
95. A.H. de Souza, M.C. Lima, C.C. Drewes, J.F. da Silva, K.C. Torres, and E.M. Pereira et al. Antiallodynic effect and side effects of Phalpha1beta, a neurotoxin from the spider Phoneutria nigriventer: comparison with omega-conotoxin MVIIA and morphine Toxicon 58 8 2011 626 633
96. A.H. de Souza, C.J. Castro Jr., F.K. Rigo, S.M. de Oliveira, R.S. Gomez, and D.M. Diniz et al. An evaluation of the antinociceptive effects of Phalpha1beta, a neurotoxin from the spider Phoneutria nigriventer, and omega-conotoxin MVIIA, a cone snail Conus magus toxin, in rat model of inflammatory and neuropathic pain Cell Mol Neurobiol 33 1 2013 59 67
97. M. Essack, V.B. Bajic, and J.A. Archer Conotoxins that confer therapeutic possibilities Mar Drugs 10 6 2012 1244 1265
98. R.M. Brady, J.B. Baell, and R.S. Norton Strategies for the development of conotoxins as new therapeutic leads Mar Drugs 11 7 2013 2293 2313
99. S. Menzler, J.A. Bikker, N. Suman-Chauhan, and D.C. Horwell Design and biological evaluation of non-peptide analogues of omega-conotoxin MVIIA Bioorg Med Chem Lett 10 4 2000 345 347
100. Z.-X. Guo, A. Cammidge, and D.C. Horwell Dendroid peptide structural mimetics of ω-conotoxin MVIIA based on a 2(1H)-quinolinone core Tetrahedron 56 2000 5169 5175
101. S. Menzler, J.A. Bikker, and D.C. Horwell Synthesis of a non-peptide analogue of omega-conotoxin MVIIA Tetrahedron Lett 39 1998 7619 7622
102. J.B. Baell, S.A. Forsyth, R.W. Gable, R.S. Norton, and R.J. Mulder Design and synthesis of type-III mimetics of omega-conotoxin GVIA J Comput Aided Mol Des 15 12 2001 1119 1136
103. J.B. Baell, P.J. Duggan, S.A. Forsyth, R.J. Lewis, Y.P. Lok, and C.I. Schroeder Synthesis and biological evaluation of nonpeptide mimetics of omega-conotoxin GVIA Bioorg Med Chem 12 15 2004 4025 4037
104. J.B. Baell, P.J. Duggan, S.A. Forsyth, R.J. Lewis, Y.P. Lok, and C. Schroeder et al. Synthesis and biological evaluation of anthranilamide-based non-peptide mimetics of ω-conotoxin GVIA Tetrahedron 62 2006 7284 7292
105. P.J. Duggan, R.J. Lewis, Y. Phei Lok, N.G. Lumsden, K.L. Tuck, and A. Yang Low molecular weight non-peptide mimics of omega-conotoxin GVIA Bioorg Med Chem Lett 19 10 2009 2763 2765
106. C.E. Tranberg, A. Yang, I. Vetter, J.R. McArthur, J.B. Baell, and R.J. Lewis et al. omega-Conotoxin GVIA mimetics that bind and inhibit neuronal Ca(v)2.2 ion channels Mar Drugs 10 10 2012 2349 2368
107. C.I. Schroeder, M.L. Smythe, and R.J. Lewis Development of small molecules that mimic the binding of omega-conotoxins at the N-type voltage-gated calcium channel Mol Divers 8 2 2004 127 134
108. B. Bear, J. Asgian, A. Termin, and N. Zimmermann Small molecules targeting sodium and calcium channels for neuropathic pain Curr Opin Drug Discov Dev 12 4 2009 543 561
109. T. Pexton, T. Moeller-Bertram, J.M. Schilling, and M.S. Wallace Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development Expert Opin Invest Drugs 20 9 2011 1277 1284
110. A. Takahara, S. Fujita, K. Moki, Y. Ono, H. Koganei, and S. Iwayama et al. Neuronal Ca2 + channel blocking action of an antihypertensive drug, cilnidipine, in IMR-32 human neuroblastoma cells Hypertens Res 26 9 2003 743 747
111. T. Yamamoto, S. Niwa, S. Iwayama, H. Koganei, S. Fujita, and T. Takeda et al. Discovery, structure-activity relationship study, and oral analgesic efficacy of cyproheptadine derivatives possessing N-type calcium channel inhibitory activity Bioorg Med Chem 14 15 2006 5333 5339
112. T. Yamamoto, S. Niwa, S. Ohno, M. Tokumasu, Y. Masuzawa, and C. Nakanishi et al. The structure-activity relationship study on 2-, 5-, and 6-position of the water soluble 1,4-dihydropyridine derivatives blocking N-type calcium channels Bioorg Med Chem Lett 18 17 2008 4813 4816
113. T. Yamamoto, S. Niwa, M. Tokumasu, T. Onishi, S. Ohno, and M. Hagihara et al. Discovery and evaluation of selective N-type calcium channel blockers: 6-unsubstituted-1,4-dihydropyridine-5-carboxylic acid derivatives Bioorg Med Chem Lett 22 11 2012 3639 3642
114. G.W. Zamponi, Z.P. Feng, L. Zhang, H. Pajouhesh, Y. Ding, and F. Belardetti et al. Scaffold-based design and synthesis of potent N-type calcium channel blockers Bioorg Med Chem Lett 19 22 2009 6467 6472
115. M.S. Lee, and T.P. Snutch Z160: a potent and state-dependent, small molecule blocker of N-type calcium channels effective in nonclinical models of neuropathic pain Pain 14 4 2013 S71
116. M.S. Lee, and T.P. Snutch Z160: a potent, state-dependent, N-type calcium channel blocker effective in animal models of neuropathic pain 4th International congress on neuropathic pain 2013 PS1
117. F. Marger, A. Gelot, A. Alloui, J. Matricon, J.F. Ferrer, and C. Barrere et al. T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome Proc Natl Acad Sci U S A 108 27 2011 11268 11273
118. H. Pajouhesh, Z.P. Feng, Y. Ding, L. Zhang, J.L. Morrison, and F. Belardetti et al. Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors Bioorg Med Chem Lett 20 4 2010 1378 1383
119. H. Pajouhesh, Z.P. Feng, L. Zhang, X. Jiang, A. Hendricson, and H. Dong et al. Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors Bioorg Med Chem Lett 22 12 2012 4153 4158
120. G.A. Doherty, P. Bhatia, T.A. Vortherms, K.C. Marsh, J.M. Wetter, and H. Mack et al. Discovery of diphenyl lactam derivatives as N-type calcium channel blockers Bioorg Med Chem Lett 22 4 2012 1716 1718
121. Heer JP, Cridland AP, Norton D. Piperazine derivatives for blocking Cav2.2 calcium channels. International PCT. Patent WO2011086377; 2011.
122. Heer JP, Cridland AP, Norton D. Piperazine derivatives for blocking Cav2.2 calcium channels. US Patent Application. Patent WO20130072499; 2013.
123. Norton D, Andreotti D, Ward SE, Profeta R, Spada S, Price HS. Piperazine derivatives as Cav2.2 calcium channel blockers. International PCT. Patent WO2012098400; 2012.
124. Beswick PJ, Gleave RJ, Hachisu S, Vile S, Bertheleme N, Ward SE. Tetrazole compounds as calcium channel blockers. International PCT. Patent WO2012004604; 2012.
125. Beswick PJ, Gleave RJ. 3-substituted 1-arylsulfonylpiperidine derivatives for the treatment of pain. international PCT. Patent WO2010091721; 2010.
126. P.P. Shao, F. Ye, P.K. Chakravarty, D.J. Varughese, J.B. Herrington, and G. Dai et al. Aminopiperidine sulfonamide Cav2.2 channel inhibitors for the treatment of chronic pain J Med Chem 55 22 2012 9847 9855
127. Chakravarty PK, Duffy JL, Shao PP. Substituted aryl sulfone derivatives as calcium channel blockers. International PCT. Patent WO2010036589; 2010.
128. Chakravarty PK, Shao PP. Substituted aryl sulfone derivatives as calcium channel blockers. International PCT. Patent WO2010036596; 2010.
129. Chakravarty PK, Ding Y, Duffy JL, Pajouhesh H, Shao PP, Tyagarajan S, et al. Substituted aryl sulfone derivatives as calcium channel blockers. US Patent 2012; US8304434.
130. N.L. Subasinghe, M.J. Wall, M.P. Winters, N. Qin, M.L. Lubin, and M.F. Finley et al. A novel series of pyrazolylpiperidine N-type calcium channel blockers Bioorg Med Chem Lett 22 12 2012 4080 4083
131. Duffy JL, Hoyt SB, London C, Stevenson CP. N-substituted oxindoline derivatives as calcium channel blockers. International PCT. Patent WO2009045381; 2009.
132. Duffy JL, Hoyt SB, London C. N-substituted oxindoline derivatives as calcium channel blockers. International PCT. Patent WO2009045386; 2009.
133. A.M. Swensen, J. Herrington, R.M. Bugianesi, G. Dai, R.J. Haedo, and K.S. Ratliff et al. Characterization of the substituted N-triazole oxindole TROX-1, a small-molecule, state-dependent inhibitor of Ca(V)2 calcium channels Mol Pharmacol 81 3 2012 488 497
134. S. Tyagarajan, P.K. Chakravarty, M. Park, B. Zhou, J.B. Herrington, and K. Ratliff et al. A potent and selective indole N-type calcium channel (Ca(v)2.2) blocker for the treatment of pain Bioorg Med Chem Lett 21 2 2011 869 873
135. C. Abbadie, O.B. McManus, S.Y. Sun, R.M. Bugianesi, G. Dai, and R.J. Haedo et al. Analgesic effects of a substituted N-triazole oxindole (TROX-1), a state-dependent, voltage-gated calcium channel 2 blocker J Pharmacol Exp Ther 334 2 2010 545 555
136. X. Beebe, D. Darczak, R.F. Henry, T. Vortherms, R. Janis, and M. Namovic et al. Synthesis and SAR of 4-aminocyclopentapyrrolidines as N-type Ca(2)(+) channel blockers with analgesic activity Bioorg Med Chem 20 13 2012 4128 4139
137. Zhang Q, Sterwart AO, Xia Z. Novel bensenesulfonamides as calcium channel blockers. International PCT. Patent WO2010083264; 2010.
138. Searle XB, Yeung MC, Schrimpf MR. Substituted octahydrocyclopenta[c] pyrroles as calcium channel modulators. International PCT. Patent WO2011149993; 2011.
139. Searle XB, Yeung MC, Didomenico S, Stewart AO, Darczak D, Schrimpf MR, et al. Novel substituted octahydrocyclopenta[c]pyrrol-4-amines as calcium channel blockers. International PCT. Patent WO2011149995; 2011.
140. Li T, Patel S, Perner RJ, Randolph JT, Schrimpf MR, Woller KR, et al. Substituted octahydropyrrolo[1,2-A]pyrazine sulfonamides as calcium channel blockers. International PCT. Patent WO2013049174; 2013.
141. Gleave RJ, Hachisu S, Page LW, Beswick PJ. Spirocyclic derivatives with affinity for calcium channels. International PCT. Patent WO2011141728; 2011.
142. Gleave RJ, Hachisu S, Page LW. Novel compounds. International PCT. Patent WO2011141729; 2011.
143. Duffy JL, Hoyt SB, London C, Stevenson CP, Ullman AM. Substituted dihydroisoquinolinone and isoquinolinedione derivatives as calcium channel blockers. International PCT. Patent WO2010017048; 2010.
144. G. Meng, N. Wu, C. Zhang, R.B. Su, X.Q. Lu, and Y. Liu et al. Analgesic activity of ZC88, a novel N-type voltage-dependent calcium channel blocker, and its modulation of morphine analgesia, tolerance and dependence Eur J Pharmacol 586 1-3 2008 130 138
145. X. Wei, H. Sun, H. Yan, C. Zhang, S. Zhang, and X. Liu et al. ZC88, a novel 4-amino piperidine analog, inhibits the growth of neuroblastoma cells through blocking hERG potassium channel Cancer Biol Ther 14 5 2013 450 457
146. S. Zhang, R. Su, C. Zhang, X. Liu, J. Li, and J. Zheng C101, a novel 4-amino-piperidine derivative selectively blocks N-type calcium channels Eur J Pharmacol 587 1-3 2008 42 47
147. Boffey RJ, Burckhardt S, Cansfield JE, Khan NM, Lawton G, Tickle D, et al. Calcium ion channel modulators and uses thereof. International PCT. Patent WO2009019508; 2009.
148. J. Mungalpara, A. Pandey, V. Jain, and C.G. Mohan Molecular modelling and QSAR analysis of some structurally diverse N-type calcium channel blockers J Mol Model 16 4 2010 629 644
149. Zalicus. NCT01655849. www.clinicaltrials.gov; 2012.
150. Zalicus. NCT01757873. www.clinicaltrials.gov; 2012.
151. Hansen S. Convergence: toning down pain. BioCentury 2010;October 18, 2010.
152. Convergence. NCT01848730. www.clinicaltrials.gov; 2013.
153. Convergence. NCT01893125. www.clinicaltrials.gov; 2013.