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.
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References
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: 1367
Andrews PLR, Rapeport WG, Sanger GJ (1988) Neuropharmacology of emesis induced by anti-cancer therapy. TIPS 9: 334
Arrowsmith J, Gams RA (1981) Dystonia with droperidol therapy. New Engl J Med 305: 227
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: 110
Cooper SM, McClelland CM, McRitchie B, Turner DH (1986) BRL 24924: a new and potent gastric motility stimulant. Br J Pharmacol [Suppl]: 383, volume 88
Costall B, Domeney AM, Naylor RJ, Tattersall FD (1986) 5-Hydroxytryptamine M-receptor antagonism to prevent cisplatin-induced emesis. Neuropharmacology 25: 959
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: 1293
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 90
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: 881
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: 1461
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: 1383
Fozard JR (1984) MDL 72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors. Naunyn-Schmiedeberg. Arch Pharmacol 326: 36
Fozard JR (1987) 5-HT3 receptors and cytotoxic drug-induced vomiting. TIPS 8: 44
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: 905
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: 163
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: 451
Indo T, Ando K (1982) Metoclopramide-induced parkinsonism: clinical characteristics of ten cases. Arch Neurol 39: 494
Ison PJ, Peroutka SJ (1986) Neurotransmitter receptor binding studies predict antiemetic efficacy and side effects. Cancer Treat Rep 70: 637
Laszlo J, Lucas VS Jr (1981) Emesis as a critical problem in chemotherapy. New Engl J Med 305: 948
Leibundgut U, Lancranjan I (1987) First results with ICS 205-930 (5-HT3 receptor antagonist) in prevention of chemotherapy-induced emesis. Lancet I: 1198
Leopold NA (1984) Prolonged metoclopramide-induced dyskinetic reaction. Neurology 34: 238
Miner WD, Sanger GJ (1986) Inhibition of cisplatin-induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism. Br J Pharmacol 88: 497
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]: 374
Miner WD, Sanger GJ, Turner DH (1987) Evidence that 5-hydroxytryptamine receptors mediate cytotoxic drug-and radiation-evoked emesis. Br J Cancer 56: 159
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: 1484
Peroutka SJ, Hamik A (1988) [3H]Quipazine labels 5-HT3 recognition sites in rat cortical membranes. Eur J Pharmacol 148: 297
Peroutka SJ, Snyder SH (1982) Antiemetics: neurotransmitter receptor binding predicts therapeutic actions. Lancet I: 658
Richardson BP, Engel G (1986) The pharmacology and function of 5-HT3 receptors. Trends Neurosci 7: 424
Schulze-Delrieu K (1981) Metoclopramide. New Engl J Med 305: 28
Seigel LJ, Longo DL (1981) The control of chemotherapyinduced emesis. Ann Intern Med 95: 352
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: 333
Strum SB, McDermed JE, Opfell RW, Riech LP (1982) Intravenous metoclopramide: an effective antiemetic in cancer chemotherapy. JAMA 247: 2683
Triozzi PL, Laszlo J (1987) Optimum management of nausea and vomiting in cancer chemotherapy. Drugs 34: 136
Wampler G (1983) The pharmacology and clinical effectiveness of phenothiazines and related drugs for managing chemotherapy-induced emesis. Drugs 25 [Suppl 1]: 35
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Hamik, A., Peroutka, S.J. Differential interactions of traditional and novel antiemetics with dopamine D2 and 5-hydroxytryptamine3 receptors. Cancer Chemother. Pharmacol. 24, 307–310 (1989). https://doi.org/10.1007/BF00304763
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DOI: https://doi.org/10.1007/BF00304763