Skip to main content

Advertisement

SpringerLink
Log in

TRPV1 Antagonists as Potential Antitussive Agents

  • Published:
Lung Aims and scope Submit manuscript

Abstract

Cough is an important defensive pulmonary reflex that removes irritants, fluids, or foreign materials from the airways. However, when cough is exceptionally intense or when it is chronic and/or nonproductive it may require pharmacologic suppression. For many patients, antitussive therapies consist of OTC products with inconsequential efficacies. On the other hand, the prescription antitussive market is dominated by older opioid drugs such as codeine. Unfortunately, “codeine-like” drugs suppress cough at equivalent doses that also often produce significant ancillary liabilities such as GI constipation, sedation, and respiratory depression. Thus, the discovery of a novel and effective antitussive drug with an improved side effect profile relative to codeine would fulfill an unmet clinical need in the treatment of cough. Afferent pulmonary nerves are endowed with a multitude of potential receptor targets, including TRPV1, that could act to attenuate cough. The evidence linking TRPV1 to cough is convincing. TRPV1 receptors are found on sensory respiratory nerves that are important in the generation of the cough reflex. Isolated pulmonary vagal afferent nerves are responsive to TRPV1 stimulation. In vivo, TRPV1 agonists such as capsaicin elicit cough when aerosolized and delivered to the lungs. Pertinent to the debate on the potential use of TRPV1 antagonist as antitussive agents are the observations that airway afferent nerves become hypersensitive in diseased and inflamed lungs. For example, the sensitivity of capsaicin-induced cough responses following upper respiratory tract infection and in airway inflammatory diseases such as asthma and COPD is increased relative to that of control responses. Indeed, we have demonstrated that TRPV1 antagonism can attenuate antigen-induced cough in the allergic guinea pig. However, it remains to be determined if the emerging pharmacologic profile of TRPV1 antagonists will translate into a novel human antitussive drug. Current efforts in clinical validation of TRPV1 antagonists revolve around various pain indications; therefore, clinical evaluation of TRPV1 antagonists as antitussive agents will have to await those outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Banner AS (1986) Cough: physiology, evaluation and treatment. Lung 164:79–92

    Article  PubMed  CAS  Google Scholar 

  2. Karlsson J-A, Fuller RW (1999) Pharmacological regulation of the cough reflex-from experimental models to antitussive effects in man. Pulm Pharmacol Ther 12:215–228

    Article  PubMed  CAS  Google Scholar 

  3. Widdicombe JG (1995) Neurophysiology of the cough reflex. Eur Respir J 8:1193–1202

    Article  PubMed  CAS  Google Scholar 

  4. Fuller RW (1990) Physiology and treatment of cough. Thorax 45:425–430

    Article  PubMed  CAS  Google Scholar 

  5. Widdicombe JG (1998) Afferent receptors in the airways and cough. Respir Physiol 114:5–15

    Article  PubMed  CAS  Google Scholar 

  6. Widdicombe J (2002) Neuroregulation of cough: implications for drug therapy. Curr Opin Pharmacol 2:256–263

    Article  PubMed  CAS  Google Scholar 

  7. Braman SS, Corrao WM (1987) Cough differential diagnosis and treatment. Clin Chest Med 8:177–182

    PubMed  CAS  Google Scholar 

  8. Hing E, Cherry DK, Woodwell BA (2006) National Ambulatory Medical Care Survey: 2004 summary. Adv Data (374):1–33

  9. McEvoy GK, Miller J, Litvak K, Dewey DR, Bollinger LA, Justice L, Kim J, Tran L, Melton GS, Young BF, Shick J, Millikan ED, Douglas PM, Shannon LP, Ford ME, Arcuri LB, Griggs TL, Reese JL (2004) Drug Information. Bethesda, MD: American Society of Health-System Pharmacist, pp 2595–2605

    Google Scholar 

  10. Lee PCL, Jawad MS, Eccles R (2000) Antitussive efficacy of dextromethorphan in cough associated with acute upper respiratory tract infection. J Pharm Pharmacol 52:1137–1142

    Article  PubMed  CAS  Google Scholar 

  11. Schroeder K, Fahey T (2002) Systematic review of randomised controlled trials of over the counter cough medicines for acute cough in adults. BMJ 324:329–331

    Article  PubMed  CAS  Google Scholar 

  12. Bolser DC, Davenport PW (2007) Codeine and cough: an ineffective gold standard. Curr Opin Allergy Clin Immunol 7:32–36

    Article  PubMed  CAS  Google Scholar 

  13. Chung KF (2007) Effective antitussives for the cough patient: An unmet need. Pulm Pharmacol Ther 20:2438–2445

    Article  CAS  Google Scholar 

  14. Barnes PJ (2007) The problem of cough and development of novel antitussives. Pulm Pharmacol Ther 20:416–422

    Article  PubMed  CAS  Google Scholar 

  15. Belvisi MG, Geppetti P (2004) Cough. 7: Current and future drugs for the treatment of chronic cough. Thorax 59:438–440

    Article  PubMed  CAS  Google Scholar 

  16. McLeod RL, Tulshian DB, Hey JA (2003) Novel pharmacological targets and progression of new antitussive drugs. Expert Opin Ther Patents 13:1501–1512

    Article  CAS  Google Scholar 

  17. McLeod RL, Parra LE, Mutter JC, Erickson CH, Carey GJ, Tulshian DB, Fawzi AB, Smith-Torhan A, Egan RW, Cuss FM, Hey JA (2001) Nociceptin inhibits cough in the guinea-pig by activation of ORL(1) receptors. Br J Pharmacol 132(6):1175–1178

    Article  PubMed  CAS  Google Scholar 

  18. Patel HJ, Birrell MA, Crispino N, Hele DJ, Venkatesan P, Barnes PJ, Yacoub MH, Belvisi MG (2003) Inhibition of guinea-pig and human sensory nerve activity and the cough reflex in guinea-pigs by cannabinoid (CB2) receptor activation. Br J Pharmacol 140:261–268

    Article  PubMed  CAS  Google Scholar 

  19. Minke B (1977) Drosophila mutant with a transducer defect. Biophys Struct Mech 1:59–64

    Article  Google Scholar 

  20. Montell C (2005) The TRP superfamily of cation channels. Sci STKE 22:1–23

    Google Scholar 

  21. Venkatachalam K, Montell C (2007) TRP channels. Annu Rev Biochem 76:387–417

    Article  PubMed  CAS  Google Scholar 

  22. Nilius B, Owsianik G, Voets T, Peters JA (2007) Transient potential cation channels in disease. Physiol Rev 87:165–217

    Article  PubMed  CAS  Google Scholar 

  23. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824

    Article  PubMed  CAS  Google Scholar 

  24. Correll CC, Phelps PT, Anthes JC, Umland S, Greenfeder S (2004) Cloning and pharmacological characterization of mouse TRPV1. Neurosci Lett 370:55–60

    Article  PubMed  CAS  Google Scholar 

  25. Hayes P, Meadows HJ, Gunthorpe MJ, Harries MH, Duckworth DM, Cairns W, Harrison DC, Clarke CE, Ellington K, Prinjha RK, Barton AJ, Medhurst AD, Smith GD, Topp S, Murdock P, Sanger GJ, Terrett J, Jenkins O, Benham CD, Randall AD, Gloger IS, Davis JB (2000) Cloning and functional expression of a human orthologue of rat vanilloid receptor-1. Pain 88:205–215

    Article  PubMed  CAS  Google Scholar 

  26. Phelps PT, Anthes JC, Correll CC (2005) Cloning and functional characterization of dog transient receptor potential vanilloid receptor-1 (TRPV1). Eur J Pharmacol 513:57–66

    Article  PubMed  CAS  Google Scholar 

  27. Savidge J, Davis C, Shah K, Colley S, Phillips E, Ranasinghe S, Winter J, Kotsonis P, Rang H, McIntyre P (2002) Cloning and functional characterization of the guinea pig vanilloid receptor 1. Neuropharmacology 43:450–456

    Article  PubMed  CAS  Google Scholar 

  28. Tominaga M, Wada M, Masu M (2001) Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia. Proc Natl Acad Sci U S A 98:6951–6956

    Article  PubMed  CAS  Google Scholar 

  29. Van Der Stelt M, Di Marzo V (2004) Endovanilloids. Putative endogenous ligands of transient receptor potential vanilloid 1 channels. Eur J Biochem 271:1827–1834

    Article  CAS  Google Scholar 

  30. Numazaki M, Tominaga T, Toyooka H, Tominaga M (2002) Direct phosphorylation of capsaicin receptor VR1 by protein kinase cepsilon and identification of two target serine residues. J Biol Chem 277:13375–13378

    Article  PubMed  CAS  Google Scholar 

  31. Sugiura T, Tominaga M, Katsuya H, Mizumura K (2002) Bradykinin lowers the threshold temperature for heat activation of vanilloid receptor 1. J Neurophysiol 88:544–548

    PubMed  CAS  Google Scholar 

  32. Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum AI, Chao MV, Julius D (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411:957–962

    Article  PubMed  CAS  Google Scholar 

  33. Rathee PK, Distler C, Obreja O, Neuhuber W, Wang GK, Wang SY, Nau C, Kress M (2002) PKA/AKAP/VR-1 module: A common link of Gs-mediated signaling to thermal hyperalgesia. J Neurosci 22:4740–4745

    PubMed  CAS  Google Scholar 

  34. Geppetti P, Materazzi S, Nicoletti P (2006) The transient receptor potential vanilloid 1: role in airway inflammation and disease. Eur J Pharmacol 533:207–214

    Article  PubMed  CAS  Google Scholar 

  35. Jia Y, Lee LY (2007) Role of TRPV receptors in respiratory diseases. Biochim Biophys Acta 1772:915-927

    PubMed  CAS  Google Scholar 

  36. Morice AH, Geppetti P (2004) Cough. 5: The type 1 vanilloid receptor: a sensory receptor for cough. Thorax 59:257–258

    Article  PubMed  CAS  Google Scholar 

  37. Watanabe N, Horie S, Michael GJ, Keir S, Spina D, Page CP, Priestley JV (2006) Immunohistochemical co-localization of transient receptor potential vanilloid (TRPV)1 and sensory neuropeptides in the guinea-pig respiratory system. Neuroscience 141:1533–1543

    Article  PubMed  CAS  Google Scholar 

  38. Jia Y, McLeod RL, Wang X, Parra L, Egan RW, Hey J (2002) Anandamide induces cough in conscious guinea pig through VR1 receptors. Br J Pharmacol 137:831–836

    Article  PubMed  CAS  Google Scholar 

  39. Tucker RC, Kagaya M, Page CP, Spina D (2001) The endogenous cannabinoid agonist, anandamide stimulates sensory nerves in guinea-pig airways. Br J Pharmacol 132:1127–1135

    Article  PubMed  CAS  Google Scholar 

  40. Carr MJ, Undem BJ (2001) Inflammation-induced plasticity of the afferent innervation of the airways. Environ Health Perspect 109(Suppl 4):567–571

    Article  PubMed  CAS  Google Scholar 

  41. Dicpinigaitis PV (2007) Experimentally induced cough. Pulm Pharmacol Ther 20:319–324

    Article  PubMed  CAS  Google Scholar 

  42. Starowicz K, Nigam S, Di Marzo V (2007) Biochemistry and pharmacology of endovanilloids. Pharmacol Ther 114:13–33

    Article  PubMed  CAS  Google Scholar 

  43. Ralevic V, Kendall DA, Jerman JC, Middlemiss DN, Smart D (2001) Cannabinoid activation of recombinant and endogenous vanilloid receptors. Eur J Pharmacol 424:211–219

    Article  PubMed  CAS  Google Scholar 

  44. Smart D, Gunthorpe MJ, Jerman JC, Nasir S, Gray J, Muir AI, Chambers JK, Randall AD, Davis JB (2000) The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol 129:227–230

    Article  PubMed  CAS  Google Scholar 

  45. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sørgård M, Di Marzo V, Julius D, Högestätt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457

    Article  PubMed  CAS  Google Scholar 

  46. Kagaya M, Lamb J, Robbins J, Page CP, Spina D (2002) Characterization of the anandamide induced depolarization of guinea-pig isolated vagus nerve. Br J Pharmacol 137:39–48

    Article  PubMed  CAS  Google Scholar 

  47. Choudry NB, Fuller RW, Pride NB (1989) Sensitivity of the human cough reflex: effect of inflammatory mediators prostaglandin E2, bradykinin, and histamine. Am Rev Respir Dis 140:137–141

    PubMed  CAS  Google Scholar 

  48. Riccio MM, Proud D, Undem BJ (1995) Enhancement of afferent nerve excitability in the airways by allergic inflammation. Pulm Pharmacol 8:181–185

    Article  PubMed  CAS  Google Scholar 

  49. Lee LY, Widdicombe JG (2001) Modulation of airway sensitivity to inhaled irritants: role of inflammatory mediators. Environ Health Perspect 109:585–589

    Article  PubMed  CAS  Google Scholar 

  50. Moore KA, Undem BJ, Weinreich D (2000) Antigen inhalation unmasks NK-2 tachykinin receptor-mediated responses in vagal afferents. Am J Respir Crit Care Med 161:232–236

    PubMed  CAS  Google Scholar 

  51. Myers AC, Kajekar R, Undem BJ (2002) Allergic inflammation-induced neuropeptide production in rapidly adapting afferent nerves in guinea pig airways. Am J Physiol Lung Cell Mol Physiol 282:L775–L781

    PubMed  CAS  Google Scholar 

  52. Lee LY, Kwong K, Lin YS, Gu Q (2002) Hypersensitivity of bronchopulmonary C-fibers induced by airway mucosal inflammation: cellular mechanisms. Pulm Pharmacol Ther 15:199–204

    Article  PubMed  CAS  Google Scholar 

  53. McLeod RL, Jia Y, McHugh NA, Fernandez X, Mingo GG, Wang X, Parra LE, Chen J, Brown D, Bolser DC, Kreutner W, Hey JA (2006) Sulfur-dioxide exposure increases TRPV1-mediated responses in nodose ganglia cells and augments cough in guinea pigs. Pulm Pharmacol Ther [Epub ahead of print]

  54. Lewis CA, Ambrose C, Banner K, Battram C, Butler K, Giddings J, Mok J, Nasra J, Winny C, Poll C (2007) Animal models of cough: literature review and presentation of a novel cigarette smoke-enhanced cough model in the guinea-pig. Pulm Pharmacol Ther 20:325–333

    Article  PubMed  CAS  Google Scholar 

  55. O’Connell F, Thomas VE, Studham JM, Pride NB, Fuller RW (1996) Capsaicin cough sensitivity increase during upper respiratory infection. Respir Med 90:279–286

    Article  PubMed  CAS  Google Scholar 

  56. Nakajima T, Nishimura Y, Nishiuma T, Kotani Y, Nakata H, Yokoyama M (2006) Cough sensitivity in pure cough variant asthma elicited using continuous capsaicin inhalation. Allergol Int 55:149–155

    Article  PubMed  Google Scholar 

  57. Weinfeld D, Ternesten-Hasseus E, Lowhagen O, Millqvist E (2002) Capsaicin cough sensitivity in allergic asthmatic patients increases during the birch pollen season. Ann Allergy Asthma Immunol 89:419–424

    Article  PubMed  Google Scholar 

  58. Doherty MJ, Mister R, Pearson MG, Calverley PMA (2000) Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease. Thorax 55:643–649

    Article  PubMed  CAS  Google Scholar 

  59. Benjamin D, Hope-Gill BD, Hilldrup S, Davies C, Newton RP, Harrison NK (2003) A study of the cough reflex in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 168:995–1002

    Article  Google Scholar 

  60. McLeod RL, Fernandez X, Correll CC, Phelps TP, Jia Y, Wang X, Hey JA (2006) TRPV1 antagonists attenuate antigen-provoked cough in ovalbumin sensitized guinea pigs. Cough 2:1–7

    Article  Google Scholar 

  61. Lai YL, Tang-Tei FC (2003) Airway hyperresponsiveness and remodeling in antigen-challenged guinea pigs. Chin J Physiol 46:9–13

    PubMed  Google Scholar 

  62. Correll CC, Palani A (2006) Advances in the development of TRPV1 antagonists. Expert Opin Ther Patents 16:783–795

    Article  CAS  Google Scholar 

  63. Rami HK, Thompson M, Stemp G, Fell S, Jerman JC, Stevens AJ, Smart D, Sargent B, Sanderson D, Randall AD, Gunthorpe MJ, Davis JB (2006) Discovery of SB-705498: A potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development. Bioorg Med Chem Lett 16:3287–3291

    Article  PubMed  CAS  Google Scholar 

  64. Doherty EM, Fotsch C, Bo Y, Chakrabarti PP, Chen N, Gavva N, Han N, Kelly MG, Kincaid J, Klionsky L, Liu Q, Ognyanov VI, Tamir R, Wang Z, Zhu J, Norman MH, Treanor JJ (2005) Discovery of potent, orally available vanilloid receptor-1 antagonists. Structure-activity relationship of N-aryl cinnamides. J Med Chem 48:71–90

    Article  CAS  Google Scholar 

  65. Doherty EM, Fotsch C, Bannon AW, Bo Y, Chen N, Dominguez C, Falsey J, Gavva NR, Katon J, Nixey T, Ognyanov VI, Pettus L, Rzasa RM, Stec M, Surapaneni S, Tamir R, Zhu J, Treanor JJ, Norman MH (2007) Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to a selection of a clinical candidate. J Med Chem 50(15):3515–3527

    Article  PubMed  CAS  Google Scholar 

  66. Wang H-L, Katon J, Balan C, Bannon AW, Bernard C, Doherty EM, Dominguez C, Gavva NR, Gore V, Ma V, Nishimura N, Surapaneni S,Tang P, Tamir R, Thiel O, Treanor JJS, Norman MH (2007) Novel vanilloid receptor-1 antagonists: 3. The identification of a second-generation clinical candidate with improved physicochemical and pharmacokinetic properties. J Med Chem 50:3528–3539

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey, 07033-0539, USA

    Robbie L. McLeod, Craig C. Correll, Yanlin Jia & John C. Anthes

Authors
  1. Robbie L. McLeod
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Craig C. Correll
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanlin Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John C. Anthes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robbie L. McLeod.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McLeod, R.L., Correll, C.C., Jia, Y. et al. TRPV1 Antagonists as Potential Antitussive Agents. Lung 186 (Suppl 1), 59–65 (2008). https://doi.org/10.1007/s00408-007-9032-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-007-9032-z

Keywords

Search

Navigation