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ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)
DOI: https://doi.org/10.15407/fz

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2022; 68(5): 89-103

CATION CHANNELS - MOLECULAR TARGETS FOR POTENTIAL DRUGS WITH AN ANALGESIC MECHANISM OF ACTION

M.Ya. Golovenko

    A.V. Bogatsky Physical-Chemical Institute of NAS of Uktaine, Odesa, Ukraine
DOI: https://doi.org/10.15407/fz68.05.089


Abstract

Ion channels ensure the functioning of the nervous system because they are involved in the depolarization of neurons, axonal conduction and the release of neurotransmitters. They are located in the membranes of all excitable tissues and are involved in the mechanisms of nociception. Modulation of ion channel signaling by small molecules can be effective in inhibiting the course of pain syndromes of various etiologies. A small number of ion channels are currently identified as potential targets for the development of antinociceptive drugs, as evidenced by medicinal chemistry data and various biophysical and pharmacological studies. This review provides examples of selective cation channel modulators as novel therapeutic agents for analgesia and prospects for the creation of innovative channel-targeted analgesic drugs.

Keywords: pain; cation channels; iGluR; 5-HT; TRP; CaV; Na; KV; ligands; analgesia

Full text: (PDF, in Ukrainian)

References

    Middleton KR, Hing E. National Hospital Ambulatory Medical Care Survey: 2004 outpatient department summary. Advance data from vital and health statistics
  1. No. 373. Hyattsville, MD: National Center for Health Statistics. 2006.
  2. Lin-Man Weng, Xuan Su, Xue-Qiang Wang. Pain symptoms in patients with Coronavirus disease (COVID-19): A literature review. J Pain Res. 2021;14:147-59. CrossRef PubMed PubMedCentral
  3. Kissin I. The development of new analgesics over the past 50 years: a lack of real breakthrough drugs. Anesth Analg. 2010;110(3):780-9. CrossRef PubMed
  4. Romanenko SV, Kostyuk PG, Kostyuk EP. Transmembrane calcium signaling: role in nociception. J Acad Med Sci Ukr. 2008;14(1):3-25.
  5. Duzhyy DE, Voitenko NV, Belan PV. Peripheral inflammation results in increased excitability of capsaicininsensitive nociceptive DRG neurons mediated by upregulation of ASICs and voltage-gated ion channels. Front Cell Neurosci. 2021 Oct 18;15:723295. CrossRef PubMed PubMedCentral
  6. Kostuk OP, Kostuk PG. Peculiarities of ion channels and modulation of their functions in neurons belonging to the nociceptive system. Neurophysiology. 2009;41(3): 241-50. CrossRef
  7. Basbaum AI, Bautista DM, Scherrer G. Cellular and molecular mechanisms of pain. Cell. 2009;139;267-84. CrossRef PubMed PubMedCentral
  8. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature. 2001 Sep 13;413(6852):203-10. CrossRef PubMed
  9. Katalin Tóth. Diversity of ion channels. J Physiol. 2021;l599(10):2603-4. CrossRef PubMed
  10. Shuba YM. Fundamentals of molecular physiology of ion channels. Kyiv: Naukova dumka, 2010.
  11. Li S, Wong AHC, Liu F. Ligand-gated ion channel interacting proteins and their role in neuroprotection. Front Cell Neurosci. 2014;8:125-32. CrossRef PubMed PubMedCentral
  12. Xu L, Ding X, Wang T. Voltage-gated sodium channels: structures, functions, and molecular modeling. Drug Discov Today. 2019;24(7);1389-97. CrossRef PubMed
  13. Stevens M, Peigneur S, Tytgat J. Neurotoxins and their binding areas on voltage-gated sodium channels. Front Pharmacol. 2011;2:71-9. CrossRef PubMed PubMedCentral
  14. Skerratt S, West C. Ion channel therapeutics for pain Channels (Austin). 2015;9(6):344-51. CrossRef PubMed PubMedCentral
  15. Musazzi L, Treccan Gi, Mallei A, Popol M. The action of antidepressants on the glutamate system: regulation of glutamate release and glutamate receptors. Biol Psychiatr. 2013;73(12):1180-8. CrossRef PubMed
  16. Yaksh N, Weber E. Effects of intrathecal NMDA and non-NMDA antagonists on acute thermal nociception and their interaction with morphine Anesthesiology. 1998;89(3):715-22. CrossRef PubMed
  17. Wang J, Goffer Y. AMPA receptors and pain-A future therapeutic intervention? Techniques in Regional Anesthesia and Pain Management. 2010; 14: 59-64. CrossRef
  18. Sean D, Donevan M, Rogawski A. GYKI 52466, a 2,3-benzodiazepine, is a highly selective, noncompetitive antagonist of AMPA/kainate receptor responses. Neuron. 1993; 10(1):51-9. CrossRef
  19. Weiss A, Ogden A, Li X. Gleason S, Calligaro D, Bleakman D, Witkin J. In vitro and in vivo studies in rats with LY293558 suggest AMPA/kainate receptor blockade as a novel potential mechanism for the therapeutic treatment of anxiety disorders. Psychopharmacology. 2006;185:240-7. CrossRef PubMed
  20. Burnstock G, Sawynok J. ATP and adenosine receptors and pain. In P. Beaulieu, D. Lussier, F. Porreca, Dickenson A H (Eds.). Pharmacol Pain. 2010:303-26. Seattle: IASP Press.
  21. Wen-jun Zhang, Hong-liang Luo, Zheng-ming Zhu. The role of P2X4 receptors in chronic pain: A potential pharmacological target. Biomed Pharmacother. 2020;129:1-9. CrossRef PubMed
  22. Schneider M, Prudic K, Pippel A. Interaction of purinergic P2X4 and P2X7 receptor subunits. Front Pharmacol. 2017;8:860-9. CrossRef PubMed PubMedCentral
  23. Wilkinson WJ, Kemp PJ. The carbon monoxide donor, CORM-2, is an antagonist of ATP-gated, human P2X4 receptors. Purinergic Sign. 2011;7:57-64. CrossRef PubMed PubMedCentral
  24. Kinga Sałat, Barbara Filipek. Antinociceptive activity of transient receptor potential channel TRPV1, TRPA1, and TRPM8 antagonists in neurogenic and neuropathic pain models in mice. J Zhejiang Univ Sci B. 2015 Mar; 16(3):167-78. CrossRef PubMed PubMedCentral
  25. Mukhopadhyay I, Kulkarni A, Aranake S, Karnik P, Shetty M, Thorat S, et al. NTransient receptor potential ankyrin 1 receptor activation in vitro and in vivo by protussive agents: GRC 17536 as a promising anti_tussive therapeutic, PLoS One. 2014;9: e97005. CrossRef PubMed PubMedCentral
  26. Petrushenko MA, Petrushenko EA, Lukyanetz EA. Structure, properties and physiological role of TRPA1 receptors. Physiol J. 2021;67(1):44-56. CrossRef
  27. Kort M, Kym P. 2 TRPV1 Antagonists: Clinical setbacks and prospects for future development. Prog Med Chem. 2012; 51:57-70. CrossRef PubMed
  28. Iegorova O, Maximyuk O, Fisyunov A, Krishtal O. Voltage-gated calcium channels: classification and pharmacological properties (Part 1). Physiol J. 2016;62(4):84-94. CrossRef PubMed
  29. Yamamoto T, Takahara A. Recent updates of N-type calcium channel blockers with therapeutic potential for neuropathic pain and stroke. Curr Top Med Chem. 2009;9:377-95. CrossRef PubMed
  30. Lee M. Z944: A first in class T-type calcium channel modulator for the treatment of pain. J Peripheral Nerv Syst. 2014;19 Suppl 2(S2):S11-2. CrossRef PubMed
  31. Nebe J, Vanegas H, Neugebauer V, Schaible HG. Omegaagatoxin IVA, a P-type calcium channel antagonist, reduces nociceptive processing in spinal cord neurons with input from the inflamed but not from the normal knee joint-an electrophysiological study in the rat in vivo. Eur J Neurosci. 1997;9:2193-201. CrossRef PubMed
  32. Dolphin AC. The α2δ subunits of voltage-gated calcium channels. BBA. 2013;1828(7):1541-9. CrossRef PubMed
  33. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006; 444(7121):894-8. CrossRef PubMed PubMedCentral
  34. 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;2:1-14. CrossRef PubMed PubMedCentral
  35. Alexandrou AJ, Brown AR, Chapman ML, Estacion M, Turner J, Wilbrey A, Payne EC, Gutteridge A, Cox PJ. Subtype selective small molecule inhibitors reveal a fundamental role for Nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release. 2016; PLoS One 11:e0152405. CrossRef PubMed PubMedCentral
  36. Binshtok AM, Bean BP, Woolf CJ. Inhibition of nociceptors by TRPV1 -mediated entry of impermeant sodium channel blockers. Nature. 2007;449(7162): 607-10. CrossRef PubMed
  37. McGaraughty S, Chu KL, Scanio MJ. A selective Nav1.8 sodium channel blocker, A-803467 [5-(4-chlorophenylN-(3,5-dimethoxyphenyl) furan-2-carboxamide], attenuates spinal neuronal activity in neuropathic rats. J Pharmacol Exp Ther. 2008; 324(3):1204-11. CrossRef PubMed
  38. Theile JW, Fuller MD, Chapman M. The Selective Nav1.7 inhibitor, PF-05089771, interacts equivalently with fast and slow inactivated Nav1.7 channels. Mol Pharmacol. 2016;90:540-8. CrossRef PubMed
  39. FockenT, Liu S, Chahal N, Dauphinais M, Grimwood ME, Chowdhury S, Hemeon I,Bichler P. Discovery of aryl sulfonamides as isoform-selective inhibitors of NaV1.7 with efficacy in rodent pain models. ACS Med Chem Lett. 2016;7(3): 277-82. CrossRef PubMed PubMedCentral
  40. Schmalhofer WA, Calhoun J, Burrows R, Bailey T, Kohler MG, Weinglass AB, et al. ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Mol Pharmacol. 2008;74(5):1476-84. CrossRef PubMed
  41. Hui K, McIntyre D, French RJ. Conotoxins as sensors of local pH and electrostatic potential in the outer vestibule of the sodium channel. J Gen Physiol. 2003;122 (1): 6379-85. CrossRef PubMed PubMedCentral
  42. Han TS, Zhang MM, Walewska A, Gruszczynski P, Robertson CR, Cheatham TE, et al. Structurally-minimized μ-conotoxin analogs as sodium channel blockers: implications for designing conopeptide-based therapeutics. Chem Med Chem. 2009;4(3):406-14. CrossRef PubMed PubMedCentral
  43. Markman JD, Dworkin RH. Ion channel targets and treatment efficacy in neuropathic pain. J Pain. 2006;7(1S) Suppl 1:538-47. CrossRef PubMed
  44. Alaa Abd-Elsayed, Markus Jackson, Steven L Gu, Kenneth Fiala, Jianguo Gu. Neuropathic pain and Kv7 voltage-gated potassium channels: The potential role of Kv7 activators in the treatment of neuropathic pain. Mol Pain. 2019;15:1-8. CrossRef PubMed PubMedCentral
  45. J Kornhuber M, Maler J, Wiltfang S, Degner D, Rüthe E. Neuronal potassium channel opening with flupirtine. Fortschr Neurol Psychiatr. 1999;67(10):466-75. CrossRef PubMed
  46. Raffa RB, Pergolizzi JV. The evolving understanding of the analgesic mechanism of action of flupirtine. J Clin Pharmac Ther, 2012;37:4-6. CrossRef PubMed
  47. Lawson K. potassium channels as targets for the management of pain. Cent Nerv Syst Agents Med Chem. 2006; 6:119-28. CrossRef
  48. Vadzyuk O B. ATP-sensitive K(+)-channels in muscle cells: features and physiological role. Ukr Biochem J. 2014;86(3):5-22. CrossRef
  49. Pan Z, Huang J, Cui W, Long C, Zhang Y, Wang H. J. Targeting hypertension with a new adenosine triphosphate-sensitive potassium channel opener iptakalim. Cardiovascul Pharmacol. 2010;56(3):215-28. CrossRef PubMed
  50. Marsh B, Acosta C, Djouhri L, Lawson SN. Leak K(+) channel mRNAs in dorsal root ganglia: relation to inflammation and spontaneous pain behavior. Mol Cell Neurosci. 2012;49:375-86. CrossRef PubMed PubMedCentral
  51. Guo Z, Cao Y-Q. Over-expression of TRESK K+ channels reduces the excitability of trigeminal ganglion nociceptors. PLOS ONE. 2014;9:e87029. CrossRef PubMed PubMedCentral
  52. Vivier D, Soussia IB, Rodrigues N, Lolignier S, Devilliers M, Chatelain FC. Development of the first two-pore domain potassium channel twik-related K+ channel 1-selective agonist possessing in vivo antinociceptive activity. J Med Chem. 2017;60:1076-88. CrossRef PubMed
  53. Calderone V. Large-conductance, Sa(2+)-activated K(+) channels: function, pharmacology and drugs. Curr Med Chem. 2002;9(14):1385-95. CrossRef PubMed
  54. Hewawasam P, Fan W, Knipe J, Moon SL, Boissard CG, Gribkoff VK, Starrett JE. The synthesis and structureactivity relationships of 4-aryl-3-aminoquinolin-2-ones: a new class of calcium-dependent, large conductance, potassium (maxi-K) channel openers targeted for post-stroke neuroprotection. Bioorg Med Chem Lett. 2002;12(13):1779-83. CrossRef
  55. Al-Karagholi MA, Ghanizada H, Nielsen CA, Hansen JM, Ashina M. Opening of BKCa channels causes migraine attacks: a new downstream target for the treatment of migraine. Pain. 2021;162(10): 2512-20. CrossRef PubMed
  56. Overington J, Al-Lazikani B, Hopkins A. How many drug targets are there? Drug Discov. 2006;5:993-6. CrossRef PubMed
  57. Dunlop J. Turning up the pace of ion channel screening in drug discovery. Neuropsychopharmacology. 2009;34:253-64. CrossRef PubMed
  58. Raju TN. The nobel chronicles. Lancet. 2000; 355:1022. CrossRef
  59. Golovenko MYa. Propoxazepam is an innovative analgesic that inhibits acute and chronic pain and has a polymodal mechanism of action. Visn NAN Ukr. 2021;4:76-90.
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