Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Combination of a Rapidly Penetrating Agonist and a Slowly Penetrating Antagonist Affords Agonist Action of Limited Duration at the Cellular Level

  • Pearce, Larry V. (Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute) ;
  • Ann, Jihyae (Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University) ;
  • Blumberg, Peter M. (Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute) ;
  • Lee, Jeewoo (Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University)
  • Received : 2019.01.22
  • Accepted : 2019.03.18
  • Published : 2019.09.01
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Abstract

The capsaicin receptor TRPV1 (transient receptor potential vanilloid 1) has been an object of intense interest for pharmacological development on account of its critical role in nociception. In the course of structure activity analysis, it has become apparent that TRPV1 ligands may vary dramatically in the rates at which they interact with TRPV1, presumably reflecting differences in their abilities to penetrate into the cell. Using a fast penetrating agonist together with an excess of a slower penetrating antagonist, we find that we can induce an agonist response of limited duration and, moreover, the duration of the agonist response remains largely independent of the absolute dose of agonist, as long as the ratio of antagonist to agonist is held constant. This general approach for limiting agonist duration under conditions in which absolute agonist dose is variable should have more general applicability.

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References

  1. Barber, M. N., Sampey, D. B. and Widdop, R. E. (1999) $AT_2$ receptor stimulation enhances antihypertensive effect of $AT_1$ receptor antagonist in hypertensive rats. Hypertension 34, 1112-1116. https://doi.org/10.1161/01.HYP.34.5.1112
  2. Bertino, J. R., Levitt, M., McCullough, J. L. and Chabner, B. (1971) New approaches to chemotherapy with folate antagonists: use of leucovorin "rescue" and enzymic folate depletion. Ann. N. Y. Acad. Sci. 186, 486-495. https://doi.org/10.1111/j.1749-6632.1971.tb47004.x
  3. Bevan, S., Hothi, S., Hughes, G., James, I. F., Rang, H. P., Shah, K., Walpole, C. S. and Yeats, J. C. (1992) Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin. Br. J. Pharmacol. 107, 544-552. https://doi.org/10.1111/j.1476-5381.1992.tb12781.x
  4. Bevan, S., Quallo, T. and Andersson, D. A. (2014) TRPV1. Handb. Exp. Pharmacol. 222, 207-245. https://doi.org/10.1007/978-3-642-54215-2_9
  5. Blumberg, P. M., Pearce, L. V. and Lee, J. (2011) TRPV1 activation is not an all-or-none event: TRPV1 partial agonism/antagonism and its regulatory modulation. Curr. Top. Med. Chem. 11, 2151-2158. https://doi.org/10.2174/156802611796904825
  6. Braun, D. C., Cao, Y., Wang, S., Garfield, S. H., Hur, G. M. and Blumberg, P. M. (2005) Role of phorbol ester localization in determining protein kinase C or RasGRP3 translocation: real-time analysis using fluorescent ligands and proteins. Mol. Cancer Ther. 4, 141-150.
  7. Broad, L. M., Keding, S. J. and Blanco, M. J. (2008) Recent progress in the development of selective TRPV1 antagonists for pain. Curr. Top. Med. Chem. 8, 1431-1441. https://doi.org/10.2174/156802608786264254
  8. Busker, R. W. and van Helden, H. P. (1998) Toxicologic evaluation of pepper spray as a possible weapon for the Dutch police force: risk assessment and efficacy. Am. J. Forensic Med. Pathol. 19, 309-316. https://doi.org/10.1097/00000433-199812000-00003
  9. Cao, E., Liao, M., Cheng, Y. and Julius, D. (2013) TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504, 113-118. https://doi.org/10.1038/nature12823
  10. Cui, M., Gosu, V., Basith, S., Hong, S. and Choi, S. (2016) Polymodal transient receptor potential vanilloid type 1 nocisensor: structure, modulators, and therapeutic applications. Adv. Prot. Chem. Struct. Biol. 104, 81-125. https://doi.org/10.1016/bs.apcsb.2015.11.005
  11. Feng, Z., Pearce, L. V., Xu, X., Yang, X., Yang, P., Blumberg, P. M. and Xie, X. Q. (2015) Structural insight into tetrameric hTRPV1 from homology modeling, molecular docking, molecular dynamics simulation, virtual screening, and bioassay validations. J. Chem. Inf. Model. 55, 572-588. https://doi.org/10.1021/ci5007189
  12. Gavva, N. R., Tamir, R., Qu, Y., Klionsky, L., Zhang, T. J., Immke. D., Wang, J., Zhu, D.; Vanderah, T. W., Porreca, F., Doherty, E. M., Norman, M. H., Wild, K. D., Bannon, A. W., Louis, J.-C. and Treanor, J. J. S. (2005) AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties. J. Pharmacol. Exp. Ther. 313, 474-484. https://doi.org/10.1124/jpet.104.079855
  13. Jung, J., Hwang, S. W., Kwak, J., Lee, S. Y., Kang, C. J., Kim, W. B., Kim, D. and Oh, U. (1999) Capsaicin bind to the intracellular domain of the capsaicin-activated ion channel. J. Neurosci. 19, 529-538. https://doi.org/10.1523/JNEUROSCI.19-02-00529.1999
  14. Kyle, D. J. and Tafesse, L. (2006) TRPV1 antagonists: a survey of the patent literature. Expert Opin. Ther. Pat. 16, 977-996. https://doi.org/10.1517/13543776.16.7.977
  15. Lazar, J., Braun, D. C., Toth, A., Wang, Y., Pearce, L. V., Pavlyukovets, V. A., Blumberg, P. M., Garfield S. H., Wincovitch, S., Choi, H. K. and Lee, J. (2006) Kinetics of penetration influence the apparent potency of vanilloids on TRPV1. Mol. Pharmacol. 69, 1166-1173. https://doi.org/10.1124/mol.105.019158
  16. Lee, J. H., Lee, Y., Ryu, H., Kang, D. W., Lee, J., Lazar, J., Pearce, L. V., Pavlyukovets, V. A., Blumberg, P. M. and Choi, S. (2011) Structural insights into transient receptor potential vanilloid type 1 (TRPV1) from homology modeling, flexible docking, and mutational studies. J. Comput. Aided Mol. Des. 25, 317-327. https://doi.org/10.1007/s10822-011-9421-5
  17. Lee, Y., Hong, S., Cui, M., Sharma, P. K., Lee, J. and Choi, S. (2015) Transient receptor potential vanilloid type 1 antagonists: a patent review (2011-2014). Expert Opin. Ther. Pat. 25, 291-318. https://doi.org/10.1517/13543776.2015.1008449
  18. Liu, L., Lo, Y. C., Chen, I. J. and Simon, S. A. (1997) The responses of rat trigeminal ganglion neurons to capsaicin and two nonpungent vanilloid receptor agonists, olvanil and glyceryl nonamide. J. Neurosci. 17, 4101-4111. https://doi.org/10.1523/JNEUROSCI.17-11-04101.1997
  19. Nagy, I., Friston, D., Valente, J. S., Torres Perez, J. V. and Andreou, A. P. (2014) Pharmacology of the capsaicin receptor, transient receptor potential vanilloid type-1 ion channel. Prog. Drug Res. 68, 39-76.
  20. Nutt, D. J. (2010) Antagonist-agonist combinations as therapies for heroin addiction: back to the future? J. Psychopharm. 24, 141-145. https://doi.org/10.1177/0269881109356129
  21. Pearce, L. V., Toth, A., Ryu, H., Kang, D. W., Choi, H.-K., Jin, M.-K., Lee, J., Blumberg, P. M. (2008) Differential modulation of agonist and antagonist structure activity relations for rat TRPV1 by cyclosporin A and other protein phosphatase inhibitors. Naunyn Schmiedebergs Arch. Pharmacol. 377, 149-157. https://doi.org/10.1007/s00210-007-0258-3
  22. Pingle, S. C., Matta, J. A. and Ahern, G. P. (2007) Capsaicin receptor: TRPV1 a promiscuous TRP channel. Handb. Exp. Pharmacol. 179, 155-171. https://doi.org/10.1007/978-3-540-34891-7_9
  23. Rohacs, T. (2015) Phosphoinositide regulation of TRPV1 revisited. Pflugers Arch. 467, 1851-1869. https://doi.org/10.1007/s00424-015-1695-3
  24. Seabrook, G. R., Sutton, K. G., Jarolimek, W., Hollingworth, G. J., Teague, S., Webb, J., Clark, N., Boyce, S., Kerby, J., Ali, Z., Chou, M., Middleton, R., Kaczorowski, G. and Jones, A. B. (2002) Functional properties of the high-affinity TRPV1 (VR1) vanilloid receptor antagonist (4-hydroxy-5-iodo-3-methoxyphenylacetate ester) iodo-resiniferatoxin. J. Pharmacol. Exp. Ther. 303, 1052-1060. https://doi.org/10.1124/jpet.102.040394
  25. Szallasi, A. and Sheta, M. (2012) Targeting TRPV1 for pain relief: limits, losers, and laurels. Expert Opin. Investig. Drugs 21, 1351-1369. https://doi.org/10.1517/13543784.2012.704021
  26. Tozer, T. N. and Rowland, M. (2006) Introduction to Pharmacokinetics and Pharmacodynamics: the Quantitative Basis of Drug Therapy. Lippincott Williams & Wilkins, Philadelphia.
  27. Valenzano, K. J., Grant, E. R., Wu, G., Hachicha, M., Schmid, L., Tafesse, L., Sun, Q., Rotshteyn, Y., Francis, J., Limberis, J., Malik, S., Whittemore, E. R. and Hodges, D. (2003) N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC), a novel, orally effectice vanilloid receptor 1 antagonist with analgesic properties: I. in vitro characterization and pharmacokinetic properties. J. Pharmacol. Exp. Ther. 306, 377-386. https://doi.org/10.1124/jpet.102.045674
  28. Voight, E. A. and Kort, M. E. (2010) Transient receptor potential vanilloid- 1 antagonists: a survey of recent patent literature. Expert Opin. Ther. Pat. 20, 1107-1122. https://doi.org/10.1517/13543776.2010.497756
  29. Wang, Q. J., Fang, T. W., Fenick, D., Garfield, S., Bienfait, B., Marquez, V. E. and Blumberg, P. M. (2000) The lipophilicity of phorbol esters as a critical factor in determining the pattern of translocation of protein kinase C delta fused to green fluorescent protein. J. Biol. Chem. 275, 12136-12146. https://doi.org/10.1074/jbc.275.16.12136
  30. Wang, Y., Toth, A., Tran, R., Szabo, T., Welter, J. D., Blumberg, P. M., Lee, J., Kang, S.-U., Lim, J.-O. and Lee, J. (2003) High-affinity partial agonists of the vanilloid receptor. Mol. Pharmacol. 64, 325-333. https://doi.org/10.1124/mol.64.2.325
  31. Winter, Z., Buhala, A., Otvos, F., Josvay, K., Vizler, C., Dombi, G. Szakonyi, G. and Olah, Z. (2013) Functionally important amino acid residues in the transient receptor potential vanilloid 1 (TRPV1) ion channel--an overview of the current mutational data. Mol. Pain 9, 30.
  32. Wrigglesworth, R., Walpole, C. S. J., Bevan, S., Campbell, E. A., Dray, A., Hughes, G. A., James, I., Masdin, K. J. and Winter, J. (1996) Analogues of capsaicin with agonist activity as novel analgesic agents: structure-activity studies. 4. Potent, orally active analgesics. J. Med. Chem. 39, 4942-4951. https://doi.org/10.1021/jm960512h

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