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. 1995 Oct;116(4):2315–2321. doi: 10.1111/j.1476-5381.1995.tb15071.x

Evaluation of the receptor selectivity of the H3 receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5-HT3 receptor revealed.

R Leurs 1, M T Tulp 1, W M Menge 1, M J Adolfs 1, O P Zuiderveld 1, H Timmerman 1
PMCID: PMC1908963  PMID: 8564266

Abstract

1. In the present study we evaluated the receptor selectivity of the potent histamine H3 receptor antagonist, iodophenpropit (IPP) in comparison with the prototype antagonist, thioperamide. 2. IPP proved to be a potent competitive H3 receptor antagonist as measured against (R)-alpha-methylhistamine-induced inhibition of electrically-evoked contractions of the guinea-pig jejunum (pA2 = 9.12 +/- 0.06, Schild slope: 1.0 +/- 0.1, n = 8). In the same assay, thioperamide was slightly less potent (pA2 = 8.9 +/- 0.2). 3. In radioligand binding studies, IPP showed a high affinity for the H3 receptor. Displacement of [125I]-IPP binding to rat cortex membranes by unlabelled IPP resulted in a Ki value of 0.97 +/- 0.06 nM (n = 3). In contrast, IPP showed only a weak affinity for the histamine H1- and H2 receptor. Displacement of [3H]-mepyramine and [125I]-iodoaminopotentidine binding to respectively guinea-pig H1- and human H2 receptors by IPP resulted in Ki values of 1.71 +/- 0.32 microM (n = 3) and 2.28 +/- 0.81 microM (n = 3). For thioperamide the affinities for the H1-, H2- and H3 receptor were respectively > 10 microM, > 10 microM and 4.3 +/- 1.6 nM (n = 7). 4. Testing IPP and thioperamide in 39 different receptor binding assays revealed that IPP showed relatively high affinity for the 5-hydroxytryptamine 5-HT3 receptor (Ki = 11 +/- 1 nM, n = 3), the alpha 2-adrenoceptor (Ki = 120 +/- 5 nM, n = 3) and the sigma receptor (Ki = 170 +/- 70 nM, n = 3). Thioperamide showed relatively high affinity for the 5-HT3 receptor (Ki = 120 +/- 30 nM, n = 3) and the sigma receptor (Ki = 180 +/- 90 nM, n = 3). 5. Due to the low density of histamine H3 receptors in the brain, the interaction of IPP with the 5-HT3-, the alpha 2- and the sigma receptor might interfere with [125I]-IPP binding to rat cortex membranes. Yet, in this preparation [125I]-IPP binding was not influenced by ondansetron, yohimbine or haloperidol.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Arrang J. M., Garbarg M., Lancelot J. C., Lecomte J. M., Pollard H., Robba M., Schunack W., Schwartz J. C. Highly potent and selective ligands for histamine H3-receptors. Nature. 1987 May 14;327(6118):117–123. doi: 10.1038/327117a0. [DOI] [PubMed] [Google Scholar]
  2. Butler A., Hill J. M., Ireland S. J., Jordan C. C., Tyers M. B. Pharmacological properties of GR38032F, a novel antagonist at 5-HT3 receptors. Br J Pharmacol. 1988 Jun;94(2):397–412. doi: 10.1111/j.1476-5381.1988.tb11542.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Eriks J. C., van der Goot H., Sterk G. J., Timmerman H. Histamine H2-receptor agonists. Synthesis, in vitro pharmacology, and qualitative structure-activity relationships of substituted 4- and 5-(2-aminoethyl)thiazoles. J Med Chem. 1992 Aug 21;35(17):3239–3246. doi: 10.1021/jm00095a021. [DOI] [PubMed] [Google Scholar]
  4. Garbarg M., Arrang J. M., Rouleau A., Ligneau X., Tuong M. D., Schwartz J. C., Ganellin C. R. S-[2-(4-imidazolyl)ethyl]isothiourea, a highly specific and potent histamine H3 receptor agonist. J Pharmacol Exp Ther. 1992 Oct;263(1):304–310. [PubMed] [Google Scholar]
  5. Hey J. A., del Prado M., Egan R. W., Kreutner W., Chapman R. W. (R)-alpha-methylhistamine augments neural, cholinergic bronchospasm in guinea pigs by histamine H1 receptor activation. Eur J Pharmacol. 1992 Feb 18;211(3):421–426. doi: 10.1016/0014-2999(92)90401-o. [DOI] [PubMed] [Google Scholar]
  6. Jansen F. P., Rademaker B., Bast A., Timmerman H. The first radiolabeled histamine H3 receptor antagonist, [125I]iodophenpropit: saturable and reversible binding to rat cortex membranes. Eur J Pharmacol. 1992 Jul 7;217(2-3):203–205. doi: 10.1016/0014-2999(92)90851-t. [DOI] [PubMed] [Google Scholar]
  7. Jansen F. P., Wu T. S., Voss H. P., Steinbusch H. W., Vollinga R. C., Rademaker B., Bast A., Timmerman H. Characterization of the binding of the first selective radiolabelled histamine H3-receptor antagonist, [125I]-iodophenpropit, to rat brain. Br J Pharmacol. 1994 Oct;113(2):355–362. doi: 10.1111/j.1476-5381.1994.tb16995.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kilpatrick G. J., Bunce K. T., Tyers M. B. 5-HT3 receptors. Med Res Rev. 1990 Oct-Dec;10(4):441–475. doi: 10.1002/med.2610100404. [DOI] [PubMed] [Google Scholar]
  9. Leurs R., Smit M. J., Menge W. M., Timmerman H. Pharmacological characterization of the human histamine H2 receptor stably expressed in Chinese hamster ovary cells. Br J Pharmacol. 1994 Jul;112(3):847–854. doi: 10.1111/j.1476-5381.1994.tb13157.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Leurs R., Timmerman H. The histamine H3-receptor: a target for developing new drugs. Prog Drug Res. 1992;39:127–165. doi: 10.1007/978-3-0348-7144-0_4. [DOI] [PubMed] [Google Scholar]
  11. Malinowska B., Schlicker E. Identification of endothelial H1, vascular H2 and cardiac presynaptic H3 receptors in the pithed rat. Naunyn Schmiedebergs Arch Pharmacol. 1993 Jan;347(1):55–60. doi: 10.1007/BF00168772. [DOI] [PubMed] [Google Scholar]
  12. Schlicker E., Kathmann M., Detzner M., Exner H. J., Göthert M. H3 receptor-mediated inhibition of noradrenaline release: an investigation into the involvement of Ca2+ and K+ ions, G protein and adenylate cyclase. Naunyn Schmiedebergs Arch Pharmacol. 1994 Jul;350(1):34–41. doi: 10.1007/BF00180008. [DOI] [PubMed] [Google Scholar]
  13. Schwartz J. C., Arrang J. M., Garbarg M., Pollard H., Ruat M. Histaminergic transmission in the mammalian brain. Physiol Rev. 1991 Jan;71(1):1–51. doi: 10.1152/physrev.1991.71.1.1. [DOI] [PubMed] [Google Scholar]
  14. Timmerman H. Histamine H3 ligands: just pharmacological tools or potential therapeutic agents? J Med Chem. 1990 Jan;33(1):4–11. doi: 10.1021/jm00163a001. [DOI] [PubMed] [Google Scholar]
  15. Traiffort E., Leurs R., Arrang J. M., Tardivel-Lacombe J., Diaz J., Schwartz J. C., Ruat M. Guinea pig histamine H1 receptor. I. Gene cloning, characterization, and tissue expression revealed by in situ hybridization. J Neurochem. 1994 Feb;62(2):507–518. doi: 10.1046/j.1471-4159.1994.62020507.x. [DOI] [PubMed] [Google Scholar]
  16. Vollinga R. C., Zuiderveld O. P., Scheerens H., Bast A., Timmerman H. A simple and rapid in vitro test system for the screening of histamine H3 ligands. Methods Find Exp Clin Pharmacol. 1992 Dec;14(10):747–751. [PubMed] [Google Scholar]
  17. Vollinga R. C., de Koning J. P., Jansen F. P., Leurs R., Menge W. M., Timmerman H. A new potent and selective histamine H3 receptor agonist, 4-(1H-imidazol-4-ylmethyl)piperidine. J Med Chem. 1994 Feb 4;37(3):332–333. doi: 10.1021/jm00029a002. [DOI] [PubMed] [Google Scholar]
  18. van Wijngaarden I., Hamminga D., van Hes R., Standaar P. J., Tipker J., Tulp M. T., Mol F., Olivier B., de Jonge A. Development of high-affinity 5-HT3 receptor antagonists. Structure-affinity relationships of novel 1,7-annelated indole derivatives. J Med Chem. 1993 Nov 12;36(23):3693–3699. doi: 10.1021/jm00075a026. [DOI] [PubMed] [Google Scholar]

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