Controlling the “Opioid Epidemic”: A Novel Chemical Entity (NCE) to Reduce or Supplant Opiate Use for Chronic Pain-Journal of Psychiatry and Brain Science-CSCIED科技核心评价数据库-手机版

Controlling the “Opioid Epidemic”: A Novel Chemical Entity (NCE) to Reduce or Supplant Opiate Use for Chronic Pain

Controlling the “Opioid Epidemic”: A Novel Chemical Entity (NCE) to Reduce or Supplant Opiate Use for Chronic Pain

ES评分 0 浏览量：705 下载量：0

DOI	10.20900/jpbs.20200022
刊名	Journal of Psychiatry and Brain Science JPBS
年，卷(期)	2020, 5(5)
作者	Boris Tabakoff*,Paula L. Hoffman,
作者单位	Department of Pharmaceutical Sciences, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E. Montview Blvd., Aurora, CO 80045, USA ;
Abstract	We report on the ongoing project “A Novel Therapeutic to Ameliorate Chronic Pain and Reduce Opiate Use.” Over 100 million adults in the U.S. suffer from intermittent or constant chronic pain, and chronic pain affects at least 10% of the world’s population. The primary pharmaceuticals for treatment of chronic pain have been natural or synthetic opioids and the use of opioids for pain treatment has resulted in what has been called an “epidemic” of opioid abuse, addiction and lethal overdoses. We have, through a process of rational drug design, generated a novel chemical entity (NCE) and have given it the name Kindolor. Kindolor is a non-opiate, non-addicting molecule that was developed specifically to simultaneously control the aberrant activity of three targets on the peripheral sensory system that are integral in the development and propagation of chronic pain. In our initial preclinical studies, we demonstrated the efficacy of Kindolor to reduce or eliminate chronic pain in five animal models. The overall goal of the project is to complete the investigational new drug (IND)-enabling preclinical studies of Kindolor, and once IND approval is gained, we will proceed to the clinical Phase Ia and 1b safety studies and a Phase 2a efficacy study. The work is in its second year, and the present report describes progress toward our overall goal of bringing our compound to a full Phase 2 ready stage.
KeyWord	chronic pain; non-opiate medication; novel chemical entity; multi-target action
基金项目
页码	-

参考文献
相关文献

1.Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1-32.

2.Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, et al. A classification of chronic pain for ICD-11. Pain. 2015;156(6):1003-7.

3.da Costa BR, Nuesch E, Kasteler R, Husni E, Welch V, Rutjes AW, et al. Oral or transdermal opioids for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2014(9):CD003115.

4.Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington (DC, US): National Academies Press (US); 2011.

5.Nahin RL. Estimates of pain prevalence and severity in adults: United States, 2012. J Pain. 2015;16(8):769-80.

6.Gaskell H, Derry S, Stannard C, Moore RA. Oxycodone for neuropathic pain in adults. Cochrane Database Syst Rev. 2016;7:CD010692.

7.Cooper TE, Chen J, Wiffen PJ, Derry S, Carr DB, Aldington D, et al. Morphine for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;5:CD011669.

8.Griebeler ML, Morey-Vargas OL, Brito JP, Tsapas A, Wang Z, Carranza Leon BG, et al. Pharmacologic interventions for painful diabetic neuropathy: An umbrella systematic review and comparative effectiveness network meta-analysis. Ann Intern Med. 2014;161(9):639-49.

9.Center for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and its Burden in the United States. Available from: https://www.cdc.gov/diabetes/data/statistics/2014statisticsreport.html. Accessed 2020 Sep 30.

10.Patil PR, Wolfe J, Said Q, Thomas J, Martin BC. Opioid use in the management of diabetic peripheral neuropathy (DPN) in a large commercially insured population. Clin J Pain. 2015;31(5):414-24.

11.Dewanjee S, Das S, Das AK, Bhattacharjee N, Dihingia A, Dua TK, et al. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur J Pharmacol. 2018;833:472-523.

12.Sadosky A, McDermott AM, Brandenburg NA, Strauss M. A review of the epidemiology of painful diabetic peripheral neuropathy, postherpetic neuralgia, and less commonly studied neuropathic pain conditions. Pain Pract. 2008;8(1):45-56.

13.Said G. Diabetic neuropathy—a review. Nat Clin Pract Neurol. 2007;3(6):331-40.

14.OʼConnor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med. 2009;122(10 Suppl):S22-32.

15.Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33(10):2285-93.

16.Habib AA, Brannagan TH, 3rd. Therapeutic strategies for diabetic neuropathy. Curr Neurol Neurosci Rep. 2010;10(2):92-100.

17.Waldfogel JM, Nesbit SA, Dy SM, Sharma R, Zhang A, Wilson LM, et al. Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review. Neurology. 2017;88(20):1958-67.

18.Franklin GM, American Academy of N. Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology. Neurology. 2014;83(14):1277-84.

19.Volkow ND, McLellan AT. Opioid Abuse in Chronic Pain--Misconceptions and Mitigation Strategies. N Engl J Med. 2016;374(13):1253-63.

20.Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm Rep. 2016;65(1):1-49.

21.Centers For Disease C, Prevention Public Health Service USDOH, Human S. Guideline for Prescribing Opioids for Chronic Pain. J Pain Palliat Care Pharmacother. 2016;30(2):138-40.

22.All Opioids Articles. Available from: https://practicalpainmanagement.com/treatments/pharmacological/opioids/. Accessed 2020 Oct 2.

23.Taneja A, Della Pasqua O, Danhof M. Challenges in translational drug research in neuropathic and inflammatory pain: the prerequisites for a new paradigm. Eur J Clin Pharmacol. 2017;73(10):1219-36.

24.Kirkpatrick DR, McEntire DM, Smith TA, Dueck NP, Kerfeld MJ, Hambsch ZJ, et al. Transmission pathways and mediators as the basis for clinical pharmacology of pain. Expert Rev Clin Pharmacol. 2016;9(10):1363-87.

25.Yekkirala AS, Roberson DP, Bean BP, Woolf CJ. Breaking barriers to novel analgesic drug development. Nat Rev Drug Discov. 2017;16(11):810.

26.Worley SL. New Directions in the Treatment of Chronic Pain: National Pain Strategy Will Guide Prevention, Management, and Research. P T. 2016;41(2):107-14.

27.Bozic I, Reiter JG, Allen B, Antal T, Chatterjee K, Shah P, et al. Evolutionary dynamics of cancer in response to targeted combination therapy. Elife. 2013;2:e00747.

28.Snell LD, Claffey DJ, Ruth JA, Valenzuela CF, Cardoso R, Wang Z, et al. Novel structure having antagonist actions at both the glycine site of the N-methyl-d-aspartate receptor and neuronal voltage-sensitive sodium channels: biochemical, electrophysiological, and behavioral characterization. J Pharmacol Exp Ther. 2000;292(1):215-27.

29.Ramsay RR, Popovic-Nikolic MR, Nikolic K, Uliassi E, Bolognesi ML. A perspective on multi-target drug discovery and design for complex diseases. Clin Transl Med. 2018;7(1):3.

30.Zimmermann GR, Lehar J, Keith CT. Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov Today. 2007;12(1-2):34-42.

31.Millan MJ. On ʻpolypharmacyʼ and multi-target agents, complementary strategies for improving the treatment of depression: a comparative appraisal. Int J Neuropsychopharmacol. 2014;17(7):1009-37.

32.Talevi A. Multi-target pharmacology: possibilities and limitations of the “skeleton key approach” from a medicinal chemist perspective. Front Pharmacol. 2015;6:205.

33.Csermely P, Agoston V, Pongor S. The efficiency of multi-target drugs: the network approach might help drug design. Trends Pharmacol Sci. 2005;26(4):178-82.

34.Wood JN, Boorman JP, Okuse K, Baker MD. Voltage-gated sodium channels and pain pathways. J Neurobiol. 2004;61(1):55-71.

35.Lai J, Porreca F, Hunter JC, Gold MS. Voltage-gated sodium channels and hyperalgesia. Annu Rev Pharmacol Toxicol. 2004;44:371-97.

36.Black JA, Liu S, Tanaka M, Cummins TR, Waxman SG. Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain. 2004;108(3):237-47.

37.Coggeshall RE, Tate S, Carlton SM. Differential expression of tetrodotoxin-resistant sodium channels Nav1.8 and Nav1.9 in normal and inflamed rats. Neurosci Lett. 2004;355(1-2):45-8.

38.Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. From genes to pain: Na v 1.7 and human pain disorders. Trends Neurosci. 2007;30(11):555-63.

39.Wang W, Gu J, Li YQ, Tao YX. Are voltage-gated sodium channels on the dorsal root ganglion involved in the development of neuropathic pain? Mol Pain. 2011;7:16.

40.Lawrence J. Nav1.7: a new channel for pain treatment. Pharm J. 2016;296:7887.

41.Eijkelkamp N, Linley JE, Baker MD, Minett MS, Cregg R, Werdehausen R, et al. Neurological perspectives on voltage-gated sodium channels. Brain. 2012;135(Pt 9):2585-612.

42.Choi JS, Waxman SG. Physiological interactions between Na(v)1.7 and Na(v)1.8 sodium channels: a computer simulation study. J Neurophysiol. 2011;106(6):3173-84.

43.Ji RR, Strichartz G. Cell signaling and the genesis of neuropathic pain. Sci STKE. 2004;2004(252):reE14.

44.Theile JW, Cummins TR. Recent developments regarding voltage-gated sodium channel blockers for the treatment of inherited and acquired neuropathic pain syndromes. Front Pharmacol. 2011;2:54.

45.Laedermann CJ, Abriel H, Decosterd I. Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes. Front Pharmacol. 2015;6:263.

46.Skolnick P, Volkow ND. Re-energizing the Development of Pain Therapeutics in Light of the Opioid Epidemic. Neuron. 2016;92(2):294-7.

47.McGaraughty S, Chu KL, Scanio MJ, Kort ME, Faltynek CR, Jarvis MF. A selective Nav1.8 sodium channel blocker, A-803467
[5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], attenuates spinal neuronal activity in neuropathic rats. J Pharmacol Exp Ther. 2008;324(3):1204-11.

48.Han Z, Jiang Y, Xiao F, Cao K, Wang DW. The effects of A-803467 on cardiac Nav1.5 channels. Eur J Pharmacol. 2015;754:52-60.

49.Emery EC, Luiz AP, Wood JN. Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief. Expert Opin Ther Targets. 2016;20(8):975-83.

50.Zakrzewska JM, Palmer J, Morisset V, Giblin GM, Obermann M, Ettlin DA, et al. Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial. Lancet Neurol. 2017;16(4):291-300.

51.Strickland IT, Martindale JC, Woodhams PL, Reeve AJ, Chessell IP, McQueen DS. Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur J Pain. 2008;12(5):564-72.

52.Klein AH, Vyshnevska A, Hartke TV, De Col R, Mankowski JL, Turnquist B, et al. Sodium Channel Nav1.8 Underlies TTX-Resistant Axonal Action Potential Conduction in Somatosensory C-Fibers of Distal Cutaneous Nerves. J Neurosci. 2017;37(20):5204-14.

53.Wang ZJ, Snell LD, Tabakoff B, Levinson SR. Inhibition of neuronal Na+ channels by the novel antiepileptic compound DCUKA: identification of the diphenylureido moiety as an inactivation modifier. Exp Neurol. 2002;178(1):129-38.

54.Song JH, Nagata K, Huang CS, Yeh JZ, Narahashi T. Differential block of two types of sodium channels by anticonvulsants. Neuroreport. 1996;7(18):3031-6.

55.Tomson T, Kenneback G. Arrhythmia, heart rate variability, and antiepileptic drugs. Epilepsia. 1997;38(11 Suppl):S48-51.

56.Tabakoff B, Ren W, Vanderlinden L, Snell LD, Matheson CJ, Wang ZJ, et al. A novel substituted aminoquinoline selectively targets voltage-sensitive sodium channel isoforms and NMDA receptor subtypes and alleviates chronic inflammatory and neuropathic pain. Eur J Pharmacol. 2016;784:1-14.

57.Shannon HE, Eberle EL, Peters SC. Comparison of the effects of anticonvulsant drugs with diverse mechanisms of action in the formalin test in rats. Neuropharmacology. 2005;48(7):1012-20.

58.Davies SN, Lodge D. Evidence for involvement of N-methylaspartate receptors in ʻwind-upʼ of class 2 neurones in the dorsal horn of the rat. Brain Res. 1987;424(2):402-6.

59.Dickenson AH, Sullivan AF. Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacology. 1987;26(8):1235-8.

60.Childers WE, Jr., Baudy RB. N-methyl-d-aspartate antagonists and neuropathic pain: the search for relief. J Med Chem. 2007;50(11):2557-62.

61.Fernandez-Montoya J, Avendano C, Negredo P. The Glutamatergic System in Primary Somatosensory Neurons and Its Involvement in Sensory Input-Dependent Plasticity. Int J Mol Sci. 2017;19(1):69.

62.Bleakman D, Alt A, Nisenbaum ES. Glutamate receptors and pain. Semin Cell Dev Biol. 2006;17(5):592-604.

63.Du J, Zhou S, Coggeshall RE, Carlton SM. N-methyl-d-aspartate-induced excitation and sensitization of normal and inflamed nociceptors. Neuroscience. 2003;118(2):547-62.

64.Jang JH, Kim DW, Sang Nam T, Se Paik K, Leem JW. Peripheral glutamate receptors contribute to mechanical hyperalgesia in a neuropathic pain model of the rat. Neuroscience. 2004;128(1):169-76.

65.Szekely JI, Torok K, Mate G. The role of ionotropic glutamate receptors in nociception with special regard to the AMPA binding sites. Curr Pharm Des. 2002;8(10):887-912.

66.Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-d-aspartate (NMDA) receptors in pain: a review. Anesth Analg. 2003;97(4):1108-16.

67.Miller KE, Hoffman EM, Sutharshan M, Schechter R. Glutamate pharmacology and metabolism in peripheral primary afferents: physiological and pathophysiological mechanisms. Pharmacol Ther. 2011;130(3):283-309.

68.Ferrari LF, Lotufo CM, Araldi D, Rodrigues MA, Macedo LP, Ferreira SH, et al. Inflammatory sensitization of nociceptors depends on activation of NMDA receptors in DRG satellite cells. Proc Natl Acad Sci U S A. 2014;111(51):18363-8.

69.Rozanski GM, Li Q, Stanley EF. Transglial transmission at the dorsal root ganglion sandwich synapse: glial cell to postsynaptic neuron communication. Eur J Neurosci. 2013a;37(8):1221-8.

70.Rozanski GM, Nath AR, Adams ME, Stanley EF. Low voltage-activated calcium channels gate transmitter release at the dorsal root ganglion sandwich synapse. J Physiol. 2013b;591(22):5575-83.

71.South SM, Kohno T, Kaspar BK, Hegarty D, Vissel B, Drake CT, et al. A conditional deletion of the NR1 subunit of the NMDA receptor in adult spinal cord dorsal horn reduces NMDA currents and injury-induced pain. J Neurosci. 2003;23(12):5031-40.

72.Karlsson U, Sjodin J, Angeby Moller K, Johansson S, Wikstrom L, Nasstrom J. Glutamate-induced currents reveal three functionally distinct NMDA receptor populations in rat dorsal horn—effects of peripheral nerve lesion and inflammation. Neuroscience. 2002;112(4):861-8.

73.Iwata H, Takasusuki T, Yamaguchi S, Hori Y. NMDA receptor 2B subunit-mediated synaptic transmission in the superficial dorsal horn of peripheral nerve-injured neuropathic mice. Brain Res. 2007;1135(1):92-101.

74.Gaunitz C, Schuttler A, Gillen C, Allgaier C. Formalin-induced changes of NMDA receptor subunit expression in the spinal cord of the rat. Amino Acids. 2002;23(1-3):177-82.

75.Wilson JA, Garry EM, Anderson HA, Rosie R, Colvin LA, Mitchell R, et al. NMDA receptor antagonist treatment at the time of nerve injury prevents injury-induced changes in spinal NR1 and NR2B subunit expression and increases the sensitivity of residual pain behaviours to subsequently administered NMDA receptor antagonists. Pain. 2005;117(3):421-32.

76.Boyce S, Wyatt A, Webb JK, O'Donnell R, Mason G, Rigby M, et al. Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn. Neuropharmacology. 1999;38(5):611-23.

77.Gogas KR. Glutamate-based therapeutic approaches: NR2B receptor antagonists. Curr Opin Pharmacol. 2006;6(1):68-74.

78.Dykstra LA, Fischer BD, Balter RE, Henry FE, Schmidt KT, Miller LL. Opioid antinociception, tolerance and dependence: interactions with the N-methyl-d-aspartate system in mice. Behav Pharmacol. 2011;22(5-6):540-7.

79.Gong K, Bhargava A, Jasmin L. GluN2B N-methyl-d-aspartate receptor and excitatory amino acid transporter 3 are upregulated in primary sensory neurons after 7 days of morphine administration in rats: implication for opiate-induced hyperalgesia. Pain. 2016;157(1):147-58.

80.Bespalov AY, Zvartau EE, Beardsley PM. Opioid-NMDA receptor interactions may clarify conditioned (associative) components of opioid analgesic tolerance. Neurosci Biobehav Rev. 2001;25(4):343-53.

81.Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science. 1991;251(4989):85-7.

82.Fischer BD, Carrigan KA, Dykstra LA. Effects of N-methyl-d-aspartate receptor antagonists on acute morphine-induced and l-methadone-induced antinociception in mice. J Pain. 2005;6(7):425-33.

83.Danysz W, Kozela E, Parsons CG, Sladek M, Bauer T, Popik P. Peripherally acting NMDA receptor/glycineB site receptor antagonists inhibit morphine tolerance. Neuropharmacology. 2005;48(3):360-71.

84.He SQ, Yang F, Perez FM, Xu Q, Shechter R, Cheong YK, et al. Tolerance develops to the antiallodynic effects of the peripherally acting opioid loperamide hydrochloride in nerve-injured rats. Pain. 2013;154(11):2477-86.

85.Lutfy K, Shen KZ, Kwon IS, Cai SX, Woodward RM, Keana JF, et al. Blockade of morphine tolerance by ACEA-1328, a novel NMDA receptor/glycine site antagonist. Eur J Pharmacol. 1995;273(1-2):187-9.

86.Lee J, Saloman JL, Weiland G, Auh QS, Chung MK, Ro JY. Functional interactions between NMDA receptors and TRPV1 in trigeminal sensory neurons mediate mechanical hyperalgesia in the rat masseter muscle. Pain. 2012b;153(7):1514-24.

87.Lee J, Chung MK, Ro JY. Activation of NMDA receptors leads to phosphorylation of TRPV1 S800 by protein kinase C and A-Kinase anchoring protein 150 in rat trigeminal ganglia. Biochem Biophys Res Commun. 2012a;424(2):358-63.

88.Finch PM, Knudsen L, Drummond PD. Reduction of allodynia in patients with complex regional pain syndrome: A double-blind placebo-controlled trial of topical ketamine. Pain. 2009;146(1-2):18-25.

89.Carlton SM. Peripheral NMDA receptors revisited—Hope floats. Pain. 2009;146(1-2):1-2.

90.Weibel R, Reiss D, Karchewski L, Gardon O, Matifas A, Filliol D, et al. Mu Opiod Receptors on Primary Afferent Nav1.8 Neurons Contribute to Opiate-Induced Analgesia: Insight from Conditional Knockout Mice. PLoS One. 2013;8(9):e74706.

91.Rodriguez-Munoz M, Sanchez-Blazquez P,Vicente-Sanchez A, Berrocoso E, Garzon J. The Mu-Opiod Receptor and the NMDA Receptor Associate in PAG Neurons: Implications in Pain Control. Neuropsychopharmacology. 2012;37(2):338-49.

92.Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesian and morphine tolerance: a current view of their possible interactions. Pain. 1995;62(3):259-74.

引用本文

Boris Tabakoff*,Paula L. Hoffman. Controlling the “Opioid Epidemic”: A Novel Chemical Entity (NCE) to Reduce or Supplant Opiate Use for Chronic Pain, Journal of Psychiatry and Brain Science. 2020; 5; (5). https://doi.org/10.20900/jpbs.20200022.

文献评论

相关学者

相关机构