Cancer Chemotherapy and Pharmacology

, Volume 24, Issue 5, pp 307–310 | Cite as

Differential interactions of traditional and novel antiemetics with dopamine D2 and 5-hydroxytryptamine3 receptors

  • Anne Hamik
  • Stephen J. Peroutka
Original Articles Antiemetic, Dopamine, 5-Hydroxytryptamine Receptors
Accepted:

Summary

The affinities of 11 drugs for both dopamine D2 and 5-hydroxytryptamine3 (5-HT3) receptor sites were determined in brain membranes. The five “traditional” antiemetics (chlorpromazine, prochlorperazine, droperidol, fluphenazine, and domperidone) displayed high affinity (<20 nM)for dopamine D2 receptors in corpus striatum but were inactive at 5-HT3 receptors. In contrast, five recently developed 5-HT3 antagonists (BRL 43694, ICS 205-930, zacopride, Lilly 278584, and MDL 72222) displayed nanomolar affinity for the 5-HT3 site but were inactive (>10,000 nM) at the dopamine D2 receptor. Metoclopramide was unique among these agents in that it was similarly potent at dopamine D2 (240±60 n M) and 5-HT3 (120±30nM) receptors.

Keywords

Dopamine Cancer Research Metoclopramide Chlorpromazine Receptor Site 
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.
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Andrews PLR, Hawthorn J (1987) Evidence for an extra-abdominal site of action for the 5-HT3 receptor antagonist BRL24924 in the inhibition of radiation-evoked emesis in the ferret. Neuropharmacology 26: 1367Google Scholar
  2. 2.
    Andrews PLR, Rapeport WG, Sanger GJ (1988) Neuropharmacology of emesis induced by anti-cancer therapy. TIPS 9: 334Google Scholar
  3. 3.
    Arrowsmith J, Gams RA (1981) Dystonia with droperidol therapy. New Engl J Med 305: 227Google Scholar
  4. 4.
    Carmichael J, Cantwell BMJ, Edwards CM, Rapeport WG, Harris AL (1988) The serotonin 3 receptor antagonist BRL 43694 and nausea and vomiting induced by cisplatin. Br Med J 297: 110Google Scholar
  5. 5.
    Cooper SM, McClelland CM, McRitchie B, Turner DH (1986) BRL 24924: a new and potent gastric motility stimulant. Br J Pharmacol [Suppl]: 383, volume 88Google Scholar
  6. 6.
    Costall B, Domeney AM, Naylor RJ, Tattersall FD (1986) 5-Hydroxytryptamine M-receptor antagonism to prevent cisplatin-induced emesis. Neuropharmacology 25: 959Google Scholar
  7. 7.
    Costall B, Kelly ME, Naylor RJ, Tan CCW, Tattersall FD (1986) 5-Hydroxytryptamine M-Receptor antagonism in the hypothalamus facilitates gastric emptying in the guinea-pig. Neuropharmacology 25: 1293Google Scholar
  8. 8.
    Costall B, Domeney AM, Gunning SJ, Naylor RJ, Tattersall FD, Tyers MB (1987) GR38032F: a potent and novel inhibitor of cisplatin-induced emesis in the ferret. Br J Pharmacol [Suppl]: 90, volume 90Google Scholar
  9. 9.
    Costall B, Domeney AM, Naylor RJ, Tyers MB (1987) Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain. Br J Pharmacol 92: 881Google Scholar
  10. 10.
    Cunningham D, Pople A, Ford HT, Hawthorn J, Gazet JC, Challoner T, Coombes RC (1987) Prevention of emesis in patients receiving cytotoxic drugs by GR38032F, a selective 5-HT3 receptor antagonist. Lancet I: 1461Google Scholar
  11. 11.
    De Haan LD, De Mulder PHM, Beex LVAM, Debruyne FMJ, Challoner T, De Pauw BE (1988) The efficacy of GR38032F, an antagonist of 5-hydroxytryptamine-3 (5-HT3) in the prophylaxis of cisplatin (CDDP)-induced nausea and vomiting. Eur J Clin Oncol 8: 1383Google Scholar
  12. 12.
    Fozard JR (1984) MDL 72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors. Naunyn-Schmiedeberg. Arch Pharmacol 326: 36Google Scholar
  13. 13.
    Fozard JR (1987) 5-HT3 receptors and cytotoxic drug-induced vomiting. TIPS 8: 44Google Scholar
  14. 14.
    Gralla RJ, Itri LM, Pisko SE, Squillante AE, Kelsen DP, Braun DW, Bordin LA, Braun TJ, Young CW (1981) Antiemetic efficacy of high-dose metoclopramide: randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. New Engl J 1 Med 305: 905Google Scholar
  15. 15.
    Gralla RJ, Tyson LB, Bordin LA, Clark RA, Kelsen DP, Kris MG, Kalman LB, Groshen S (1984) Antiemetic therapy: a review of recent studies and a report of a random assignment trial comparing metoclopramide with delta-9-tetrahydrocannabinol. Cancer Treat Rep 68: 163Google Scholar
  16. 16.
    Harrington RA, Hamilton CW, Brogden RN, Linkewich JA, Romankiewicz JA, Heel RC (1983) Metoclopramide: an updated review of its pharmacological properties and clinical use. Drugs 25: 451Google Scholar
  17. 17.
    Indo T, Ando K (1982) Metoclopramide-induced parkinsonism: clinical characteristics of ten cases. Arch Neurol 39: 494Google Scholar
  18. 18.
    Ison PJ, Peroutka SJ (1986) Neurotransmitter receptor binding studies predict antiemetic efficacy and side effects. Cancer Treat Rep 70: 637Google Scholar
  19. 19.
    Laszlo J, Lucas VS Jr (1981) Emesis as a critical problem in chemotherapy. New Engl J Med 305: 948Google Scholar
  20. 20.
    Leibundgut U, Lancranjan I (1987) First results with ICS 205-930 (5-HT3 receptor antagonist) in prevention of chemotherapy-induced emesis. Lancet I: 1198Google Scholar
  21. 21.
    Leopold NA (1984) Prolonged metoclopramide-induced dyskinetic reaction. Neurology 34: 238Google Scholar
  22. 22.
    Miner WD, Sanger GJ (1986) Inhibition of cisplatin-induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism. Br J Pharmacol 88: 497Google Scholar
  23. 23.
    Miner WD, Sanger GJ, Turner DH (1986) Comparison of the effect of BRL 24924, metoclopramide and domperidone on cisplatin-induced emesis in the ferret. Br J Cancer [Suppl 1]: 374Google Scholar
  24. 24.
    Miner WD, Sanger GJ, Turner DH (1987) Evidence that 5-hydroxytryptamine receptors mediate cytotoxic drug-and radiation-evoked emesis. Br J Cancer 56: 159Google Scholar
  25. 25.
    Norman AB, Battaglia G, Creese I (1987) Differential recovery rates of rat D2 dopamine receptors as a function of aging and chronic reserpine treatment following irreversible modification: a key to receptor regulatory mechanisms. J Neurosci 7: 1484Google Scholar
  26. 26.
    Peroutka SJ, Hamik A (1988) [3H]Quipazine labels 5-HT3 recognition sites in rat cortical membranes. Eur J Pharmacol 148: 297Google Scholar
  27. 27.
    Peroutka SJ, Snyder SH (1982) Antiemetics: neurotransmitter receptor binding predicts therapeutic actions. Lancet I: 658Google Scholar
  28. 28.
    Richardson BP, Engel G (1986) The pharmacology and function of 5-HT3 receptors. Trends Neurosci 7: 424Google Scholar
  29. 29.
    Schulze-Delrieu K (1981) Metoclopramide. New Engl J Med 305: 28Google Scholar
  30. 30.
    Seigel LJ, Longo DL (1981) The control of chemotherapyinduced emesis. Ann Intern Med 95: 352Google Scholar
  31. 31.
    Stables R, Andrews PLR, Bailey HE, Costall B, Gunning SJ, Hawthorn J, Naylor RJ, Tyers MB (1987) Antiemetic properties of the 5HT3-receptor antagonist GR38032F. Cancer Treat Rev 14: 333Google Scholar
  32. 32.
    Strum SB, McDermed JE, Opfell RW, Riech LP (1982) Intravenous metoclopramide: an effective antiemetic in cancer chemotherapy. JAMA 247: 2683Google Scholar
  33. 33.
    Triozzi PL, Laszlo J (1987) Optimum management of nausea and vomiting in cancer chemotherapy. Drugs 34: 136Google Scholar
  34. 34.
    Wampler G (1983) The pharmacology and clinical effectiveness of phenothiazines and related drugs for managing chemotherapy-induced emesis. Drugs 25 [Suppl 1]: 35Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • Anne Hamik
    • 1
  • Stephen J. Peroutka
    • 1
  1. 1.Department of NeurologyStanford University Medical CenterStanfordUSA

Personalised recommendations