, Volume 60, Issue 3, pp 533–546 | Cite as

Potential of Substance P Antagonists as Antiemetics

  • Pierre Diemunsch
  • Laurent Grélot
Leading Article


The introduction of serotonin 5-HT3 receptor antagonists into clinical practice allowed for a dramatic improvement in the management of nausea and vomiting. Despite this, postoperative and chemotherapy-induced emesis remains a significant, unresolved issue in many patients even when a combination of antiemetic drugs is used. Numerous neurotransmitters have been implicated in triggering emesis; however, the tachykinin substance P, by virtue of its localisation within both the gastrointestinal vagal afferent nerve fibres and brainstem emetic circuitry, and its ability to induce vomiting when administered intravenously, is thought to play a key role in emetic responses. Because substance P is the most likely endogenous ligand for the neurokinin-1 (NK1) receptor, the development of nonpeptide NK1 receptor antagonists led scientists to evaluate these compounds as antiemetics. The five NK1 receptor inhibitors that have been studied initially in humans are: vofopitant (GR-205171), CP-122721, ezlopitant (CJ-11974), MK-869 (L-754030) and its prodrug L-758298. Except for monotherapy in acute cisplatin-induced emesis, this new class of drugs has proven to be highly effective in the control of both chemotherapy-induced nausea and vomiting, and postoperative nausea and vomiting. No major adverse event was reported in the preliminary trials. Further investigation is mandatory in order to assess the optimal treatment regimen and to make sure the wide spectrum activity of the NK1 receptor inhibitors does not cause significant adverse effects in the context of the treatment of nausea and vomiting.


Ondansetron Granisetron Nucleus Tractus Solitarius Acute Emesis Antiemetic Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors thank Jocelyne Roman for preparation of the figures and Heidi Cahen for her expertise in medical English translation.


  1. 1.
    Bianchi AL, Grélot L. An overwiew of emesis. In: Bianchi AL, Grélot L, Miller AD, et al., editors. New vistas on mechanisms and control of emesis. Vol. 223. London: Colloque INSERM/John Libbey Eurotext Ltd, 1992: 3–9Google Scholar
  2. 2.
    Grélot L, Miller AD. Vomiting: its in and outs. NIPS 1994; 9: 142–6Google Scholar
  3. 3.
    Lucot JB. 5-HT1Areceptor agonists as anti-emetic. In: Reynolds DJM, Andrew PLR, Davis CJ, editors. Serotonin and the scientific basis of anti-emetic therapy. Oxford: Oxford Clinical Communications, 1995: 222–7Google Scholar
  4. 4.
    Rudd JA, Naylor RJ. Opioid receptor involvement in emesis and anti-emesis. In: Reynolds DJM, Andrew PLR, Davis CJ, editors. Serotonin and the scientific basis of anti-emetic therapy. Oxford: Oxford Clinical Communications, 1995: 209–19Google Scholar
  5. 5.
    Carpenter DO, Briggs DB, Strominger N. Peptide induced emesis in dogs. Behav Brain Res 1984; 11: 277–81PubMedCrossRefGoogle Scholar
  6. 6.
    Andrews PLR, Bhandari P. Resinferatoxin, an ultrapotent capsaicin analogue, has anti-emetic properties in the ferret. Neuropharmacol 1993; 32: 799–806CrossRefGoogle Scholar
  7. 7.
    Maggi CA. The mammalian tachykinin receptors. Gen Pharmacol 1995; 26: 911–44PubMedCrossRefGoogle Scholar
  8. 8.
    Henry JL. Discussion of nomenclature for TKs and tachykin receptor: substance P and neurokinins. New York: Springer-Verlag, 1987Google Scholar
  9. 9.
    McLean S, Ganong A, Seymour PA, et al. Pharmacology of CP-99,994: a non-peptide antagonist of the tachykinin NK-1 receptor. J Pharmacol Exp Ther 1993; 267: 472–9PubMedGoogle Scholar
  10. 10.
    Quartara L, Maggi CA. The tachykinin NK1 receptor. Part 1: ligands and mechanisms of cellular activation. Neuropeptides 1997; 31: 537–63Google Scholar
  11. 11.
    McLean S. Nonpeptide antagonists of the NK1 tachykinin receptor. Med Res Rev 1996; 16: 297–317PubMedCrossRefGoogle Scholar
  12. 12.
    Rupniak NMJ, Boyce S, Williams AR, et al. Antinociceptive activity of NK1 receptor antagonists: nonspecific effects of racemic RP 67, 580. Br J Pharmacol 1993; 110: 1607–13PubMedCrossRefGoogle Scholar
  13. 13.
    McLean S, Ganong A, Seymour PA, et al. Characterization of CP-122,721, a nonpeptide antagonist of the neurokinin NK1 receptor. J Pharmacol Exp Ther 1996; 277: 900–8PubMedGoogle Scholar
  14. 14.
    Gardner CJ, Armour DR, Beattie DT, et al. A novel antagonist with high affinity for the tachykinin NK1 receptor, and potent broad-spectrum anti-emetic activity. Regul Pept 1996; 65: 45–53PubMedCrossRefGoogle Scholar
  15. 15.
    Hale JJ, Mills SG, MacCoss M, et al. Structural optimization affording 2-(R)-(l-(R)-(3,5-Bis(trifluoromethyl)phenylethoxy)-3(S)-(4fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl) methylmorpholine a potent orally active, long-acting morpholine acetal human NK-1 receptor antagonist. J Med Chem 1998; 41:4607–14PubMedCrossRefGoogle Scholar
  16. 16.
    Bountra C, Bunce KT, Dale T, et al. Anti-emetic profile of a non-peptide, neurokinin NK1 receptor anatagonist, CP-99,994, in ferrets. Eur J Pharmacol 1993; 249: R3–4PubMedCrossRefGoogle Scholar
  17. 17.
    Chen Y, Saito H, Matsuki N. Ethanol-induced emesis in the house musk shrew, Suncus murinus. Life Sci 1997; 60: 253–61PubMedCrossRefGoogle Scholar
  18. 18.
    Lucot JB, Obach RS, McLean S, et al. The effect of CP-99994 on the responses of provocative motion in the cat. Br J Pharmacol 1997; 120: 116–20PubMedCrossRefGoogle Scholar
  19. 19.
    Rudd JA, Jordan CC, Naylor RJ. The action of the NK1 receptor antagonist, CP-99,994 in antagonizing the acute and delayed emesis induced by cisplatin in ferret. Br J Pharmacol 1996; 119:931–6PubMedCrossRefGoogle Scholar
  20. 20.
    Rupniak NM, Tattersall FD, Williams AR, et al. In vitro and in vivo predictors of the anti-emetic activity of tachykinin NK1 receptor antagonists. Eur J Pharmacol 1997; 326: 201–9PubMedCrossRefGoogle Scholar
  21. 21.
    Tattersall DF, Rycroft W, Hargreaves RJ, et al. The tachykinin NK1 receptor antagonist CP-99,994 attenuates cisplatin induced emesis in ferret. Eur J Pharmacol 1993; 250: R5–6PubMedCrossRefGoogle Scholar
  22. 22.
    Tattersall FD, Rycroft W, Hill RG, et al. Enantiospecific inhibition of apomorphine-induced emesis in the ferret by the neu-rokinin1 receptor antagonist CP-99, 994. Neuropharmacology 1995; 33: 259–60CrossRefGoogle Scholar
  23. 23.
    Tattersall FD, Rycroft W, Marmont N, et al. Enantiospecific inhibition of emesis induced by nicotine in the house musk shrew (Suncus murinus) by the neurokinin1 (NK1) receptor antagonist CP-99, 994. Neuropharmacology 1995; 34: 1697–9PubMedCrossRefGoogle Scholar
  24. 24.
    Watson JW, Nagahisa A, Lucot JB, et al. The tachykinins and emesis: towards complete control? In: Reynolds DJM, Andrew PLR, Davis CJ, editors. Serotonin and the scientific basis of anti-emetic therapy. Oxford: Oxford Clinical Communications, 1995: 233–8Google Scholar
  25. 25.
    Watson JW, Gonsalves SF, Fossa AA, et al. The anti-emetic effects of CP-99,994 in the ferret and the dog: role of the NK1 receptor. Br J Pharmacol 1995; 115: 84–94PubMedCrossRefGoogle Scholar
  26. 26.
    Gonsalves SF, Watson JW, Ashton C. Broad spectrum antiemetic effects of CP-122,721, a tachykinin NK1 receptor antagonist, in ferrets. Eur J Pharmacol 1996; 305: 181–5PubMedCrossRefGoogle Scholar
  27. 27.
    Gardner CJ, Twissell DJ, Dale TJ, et al. The broad-spectrum anti-emetic activity of the novel non-peptide tachykinin NK1 receptor, GR 203040. Br JPharmacol 1995; 116: 3158–63CrossRefGoogle Scholar
  28. 28.
    Amour DR, Chung KML, Congreve B, et al. Tetrazole NK1 receptor antagonists: the identification of an exceptionally potent orally active antiemetic compound. Bioorg Med Chem 1996; 6: 1015–20CrossRefGoogle Scholar
  29. 29.
    Grélot L, Dapzol J, Estève E, et al. Potent inhibition of acute and delayed cisplatin-induced nausea and vomiting in piglets treated by GR205171, a novel highly selective NK1 receptor antagonist. Br J Pharmacol 1998; 124: 1643–50PubMedCrossRefGoogle Scholar
  30. 30.
    Furukawa N, Fukuda H, Hatano M, et al. A neurokinin 1 receptor antagonist reduced hypersalivation and gastric contractility related to emesis in dogs. Am J Physiol 1998; G1193-201Google Scholar
  31. 31.
    Fukuda H, Koga T, Furukawa N, et al. The tachykinin NK1 receptor antagonist GR 205171 prevents vagal stimulation-induced retching but not neuronal transmission from emetic vagal afferents to solitary nucleus neurons in dogs. Brain Res 1998; 802: 221–31PubMedCrossRefGoogle Scholar
  32. 32.
    Tattersall FD, Rycroft W, Francis B, et al. Tachykinins NK1 receptor antagonists act centrally to inhibit emesis induced by the chemotherapeutic agent cisplatin in ferrets. Neuropharmacology 1996; 35: 1121–9PubMedCrossRefGoogle Scholar
  33. 33.
    Singh L, Field MJ, Hughes J, et al. The tachykinin NK1 receptor antagonist PD 154075 blocks cisplatin-induced delayed emesis in the ferret. Eur J Pharmacol 1997; 321: 209–16PubMedCrossRefGoogle Scholar
  34. 34.
    Saito R, Suehiro Y, Ariumi H, et al. Anti-emetic effects of a novel NK-1 receptor antagonist HSP-117 in ferrets. Neurosci Lett 1998; 254: 169–72PubMedCrossRefGoogle Scholar
  35. 35.
    Minami M, Endo T, Kikuchi K, et al. Antiemetic effects of sendide, a peptide tachykinin NK1 receptor antagonist, in the ferret. Eur J Pharmacol 1998; 363: 49–55PubMedCrossRefGoogle Scholar
  36. 36.
    Gardner CJ, Bountra C, Bunce KT, et al. Anti-emetic activity of neurokinin NK1 receptor antagonists is mediated centrally in the ferret [abstract]. Br J Pharmacol 1994; 112: 516PGoogle Scholar
  37. 37.
    Rupniak NMJ, Carlson E, Boyce S, et al. Enantioselective inhibition of the formalin paw late phase by the NK1 receptor antagonist L-733,060 in gerbils. Pain 1996; 67: 189–95PubMedCrossRefGoogle Scholar
  38. 38.
    Milano S, Grélot L, Blower P, et al. The piglet as a suitable animal model for studying the delayed phase of chemotherapy-induced delayed emesis. J Pharmacol Exp Ther 1995; 274: 951–61PubMedGoogle Scholar
  39. 39.
    Grélot L, Milano S, Le Stunff H, et al. Repeated administration of the 5-HT3 receptor antagonist Granisetron reduces the incidence of delayed cisplatin-induced emesis in the piglet. J Pharmacol Exp Ther 1996; 279: 255–61PubMedGoogle Scholar
  40. 40.
    Gardner C, Perren M. Inhibition of anaesthetic-induced emesis by a NK1 or 5-HT3 receptor antagonist in the house musk shrew, Suncus murinus. Neuropharmacology 1998; 37: 1643–4PubMedCrossRefGoogle Scholar
  41. 41.
    McAllister KH, Pratt JA. GR205171 blocks apomorphine and amphetamine-induced conditioned taste aversions. Eur J Pharmacol 1998; 353: 141–8PubMedCrossRefGoogle Scholar
  42. 42.
    Matsuki N, Toyoda H, Saito H. Role of substance P in emesis. Folia Pharmacol Jpn 1996; 108 Suppl. 1: 133–8CrossRefGoogle Scholar
  43. 43.
    Shiroshita Y, Koga T, Fukuda H. Capsaicin in 4th ventricle abolishes retching and transmission of emetic vagal afferents to solitary nucleus neurons. Eur J Pharmacol 1997; 339:183–92PubMedCrossRefGoogle Scholar
  44. 44.
    Davidson JS, Oland L, Boissonade F The effects of centrally injected NK1 receptor antagonists on emesis in the ferret [abstract]. Gastroenterology 1995; 108: A589Google Scholar
  45. 45.
    Yates BJ, Grélot L, Kerman IA, et al. Organisation of the vestibular inputs to nucleus tractus solitarius and adjacent structures in cat brain stem. Am J Physiol 1994; 267: R974–83PubMedGoogle Scholar
  46. 46.
    Leslie RA. Neuroactive substances in the dorsal vagal complex of the medulla oblongata: nucleus of the tractus solitarius, area postrema and dorsal motor nucleus of the vagus. Neurochem Int 1985;7: 191–211PubMedCrossRefGoogle Scholar
  47. 47.
    Dockray GJ, Sharkey KA. Neurochemistry of visceral afferent neurones. Prog Brain Res 1986; 67: 133–48PubMedCrossRefGoogle Scholar
  48. 48.
    Dockray GJ, Green T, Varro A. The afferent peptidergic innervation of the upper gastrointestinal tract. In: Singer MV, Goebell H, editors. Nerves and GI tract. Falk Symposium 50. Lancaster: Kluwer Academic 1989: 105–22Google Scholar
  49. 49.
    Fasth KJ, Bergstrom M, Kilpatrick G, et al. Brain uptake and receptor binding of two 11C-labelled selective high affinity NK1-antagonists, GR203040 and GR 205171. J Label Compounds Radiopharm 1997; 40: 665–7Google Scholar
  50. 50.
    Sakurada T, Sakudara C, Tan-No K, et al. Neurokinin receptor antagonists; therapeutic potential in the treatment of pain syndromes. CNS Drugs 1997; 8: 436–47CrossRefGoogle Scholar
  51. 51.
    Palmer JL, Fumoleau B, Bryssine P, et al. Preliminary pharma-cokinetics of the NK1 receptor antagonist GR205171 in patients with chemotherapy induced or postoperative nausea and vomiting [abstract]. Chester: British Pharmacological Society, Apr 1998Google Scholar
  52. 52.
    Hesketh PJ, Gralla RJ, Webb RT, et al. Randomized phase II study of the neurokinin 1 receptor antagonist CJ-11,974 in the control of cisplatin-induced emesis. J Clin Oncol 1999; 17: 338–43PubMedGoogle Scholar
  53. 53.
    Navari RM, Reinhardt RR, Gralla RJ, et al. Reduction of cisplatin-induced emesis by a selective neurokinin1-receptor antagonist. N Engl J Med 1999; 340: 190–5PubMedCrossRefGoogle Scholar
  54. 54.
    Fumoleau P, Graham E, Giovanni M, et al. Control of acute cisplatin-induced emesis and nausea with the NK1 receptor antagonist GR205171 in combination with ondansetron [abstract]. iProceedings of the 34th Annual Meeting of the American Society of Clinical Oncology: 1998 May 16–18; Los Angeles (CA), 17: 225Google Scholar
  55. 55.
    Diemunsch P, Schoeffler P, Bryssine B, et al. Anti-emetic activity of the NK1 receptor antagonist GR205171 in the treatment of established PONV following major gynaecological surgery. Br J Anaesth 1999; 82: 274–6PubMedCrossRefGoogle Scholar
  56. 56.
    Kris MG, Radford JE, Pizzo B A, et al. Use of an NK1 receptor antagonist to prevent delayed emesis after cisplatin. J Natl Cancer Institute 1997; 89: 817–8CrossRefGoogle Scholar
  57. 57.
    Gesztesi ZS, Song D, White PR Comparison of a new NK1 antagonist (CP122,721) to ondansetron in the prevention of postoperative nausea and vomiting [abstract]. Anesth Analg 1998; 86 Suppl. 2: S32CrossRefGoogle Scholar
  58. 58.
    Van Belle S, Cocquyt V, De Smet M, et al. Comparison of a neurokinin1 antagonist, L-758,298, to ondansetron in the prevention of cisplatin-induced emesis [abstract]. Proceedings of the 34th Annual Meeting of the American Society of Clinical Oncology: 1998 May 16–18; Los Angeles(CA), 1998; 17: 189Google Scholar
  59. 59.
    Dionne RA, Max MB, Gordon SM, et al. The substance P receptor antagonist CP-99,994 reduces acute postoperative pain. Clin Pharmacol Ther 1998; 64: 562–8PubMedCrossRefGoogle Scholar
  60. 60.
    Diemunsch P, Korttila K, Kovac A. Current therapy for management of postoperative nausea and vomiting: the 5-HT3 receptor antagonists. Ambulatory Surg 1999; 7: 111–22CrossRefGoogle Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  1. 1.Department of Anaesthesiology, Head of Experimental Anaesthesia Unit, IRCADHôpitaux Universitaires de StrasbourgStrasbourgFrance
  2. 2.UPRES - EA ‘DPAP’, Faculty of Sports ScienceUniversité de la MéditerranéeMarseilleFrance

Personalised recommendations