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. 1992 May;106(1):123–126. doi: 10.1111/j.1476-5381.1992.tb14303.x

FR 113680: a novel tripeptide substance P antagonist with NK1 receptor selectivity.

H Morimoto 1, M Murai 1, Y Maeda 1, D Hagiwara 1, H Miyake 1, M Matsuo 1, T Fujii 1
PMCID: PMC1907453  PMID: 1380378

Abstract

1. We have discovered a novel tripeptide substance P (SP) antagonist, FR 113680 [N alpha-[N alpha-(N alpha-acetyl-L-threonyl)-N'-formyl-D- tryptophyl]-N-methyl-N-phenylmethyl-L-phenylalaninamide]. In binding experiments, FR 113680 inhibited [3H]-SP binding to guinea-pig lung membranes (NK1) in a competitive manner but had not effect on [3H]-SP binding to rat cerebral cortical membranes (NK1), [3H]-neurokinin A ([3H]-NKA) binding to rat duodenum smooth muscle membranes (NK2) and [3H]-eledoisin (Ele) binding to rat cerebral cortical membranes (NK3). 2. In bioassay experiments, FR 113680 dose-dependently inhibited SP-induced guinea-pig ileum contraction (NK1), but did not inhibit either NKA-induced rat vas deferens contraction (NK2) or neurokinin B (NKB)-induced contraction of rat portal vein (NK3). According to Schild plot analysis, the inhibitory effect of FR 113680 on SP-induced guinea-pig ileum contraction is competitive and the pA2 value is 7.53. 3. The inactivity of FR 113680 on NK1 receptors in rat compared to guinea-pig may represent species-specific forms of the NK1 receptor. 4. These findings suggest that FR 113680 interacts selectively with the NK1 neurokinin receptor.

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Selected References

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  1. ARUNLAKSHANA O., SCHILD H. O. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. doi: 10.1111/j.1476-5381.1959.tb00928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barnes P. J. Neuropeptides and asthma. Am Rev Respir Dis. 1991 Mar;143(3 Pt 2):S28–S32. doi: 10.1164/ajrccm/143.3_Pt_2.S28. [DOI] [PubMed] [Google Scholar]
  3. Beresford I. J., Birch P. J., Hagan R. M., Ireland S. J. Investigation into species variants in tachykinin NK1 receptors by use of the non-peptide antagonist, CP-96,345. Br J Pharmacol. 1991 Oct;104(2):292–293. doi: 10.1111/j.1476-5381.1991.tb12423.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bergström L., Beaujouan J. C., Torrens Y., Saffroy M., Glowinski J., Lavielle S., Chassaing G., Marquet A., D'Orleans-Juste P., Dion S. 3H-neurokinin A labels a specific tachykinin-binding site in the rat duodenal smooth muscle. Mol Pharmacol. 1987 Dec;32(6):764–771. [PubMed] [Google Scholar]
  5. Bergström L., Torrens Y., Saffroy M., Beaujouan J. C., Lavielle S., Chassaing G., Morgat J. L., Glowinski J., Marquet A. [3H]neurokinin B and 125I-Bolton Hunter eledoisin label identical tachykinin binding sites in the rat brain. J Neurochem. 1987 Jan;48(1):125–133. doi: 10.1111/j.1471-4159.1987.tb13136.x. [DOI] [PubMed] [Google Scholar]
  6. Castairs J. R., Barnes P. J. Autoradiographic mapping of substance P receptors in lung. Eur J Pharmacol. 1986 Aug 15;127(3):295–296. doi: 10.1016/0014-2999(86)90380-8. [DOI] [PubMed] [Google Scholar]
  7. Dion S., D'Orléans-Juste P., Drapeau G., Rhaleb N. E., Rouissi N., Tousignant C., Regoli D. Characterization of neurokinin receptors in various isolated organs by the use of selective agonists. Life Sci. 1987 Nov 16;41(20):2269–2278. doi: 10.1016/0024-3205(87)90538-8. [DOI] [PubMed] [Google Scholar]
  8. Fardin V., Garret C. Species differences between [3H] substance P binding in rat and guinea-pig shown by the use of peptide agonists and antagonists. Eur J Pharmacol. 1991 Aug 29;201(2-3):231–234. doi: 10.1016/0014-2999(91)90350-y. [DOI] [PubMed] [Google Scholar]
  9. Gitter B. D., Waters D. C., Bruns R. F., Mason N. R., Nixon J. A., Howbert J. J. Species differences in affinities of non-peptide antagonists for substance P receptors. Eur J Pharmacol. 1991 May 17;197(2-3):237–238. doi: 10.1016/0014-2999(91)90532-u. [DOI] [PubMed] [Google Scholar]
  10. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  11. Lee C. M., Campbell N. J., Williams B. J., Iversen L. L. Multiple tachykinin binding sites in peripheral tissues and in brain. Eur J Pharmacol. 1986 Nov 4;130(3):209–217. doi: 10.1016/0014-2999(86)90270-0. [DOI] [PubMed] [Google Scholar]
  12. Lee C. M., Javitch J. A., Snyder S. H. 3h-substance P binding to salivary gland membranes. Regulation by guanyl nucleotides and divalent cations. Mol Pharmacol. 1983 May;23(3):563–569. [PubMed] [Google Scholar]
  13. Lundberg J. M., Saria A. Capsaicin-induced desensitization of airway mucosa to cigarette smoke, mechanical and chemical irritants. Nature. 1983 Mar 17;302(5905):251–253. doi: 10.1038/302251a0. [DOI] [PubMed] [Google Scholar]
  14. Maggi C. A., Giuliani S., Santicioli P., Regoli D., Meli A. Peripheral effects of neurokinins: functional evidence for the existence of multiple receptors. J Auton Pharmacol. 1987 Mar;7(1):11–32. doi: 10.1111/j.1474-8673.1987.tb00130.x. [DOI] [PubMed] [Google Scholar]
  15. Mastrangelo D., Mathison R., Huggel H. J., Dion S., D'Orléans-Juste P., Rhaleb N. E., Drapeau G., Rovero P., Regoli D. The rat isolated portal vein: a preparation sensitive to neurokinins, particularly neurokinin B. Eur J Pharmacol. 1987 Feb 24;134(3):321–326. doi: 10.1016/0014-2999(87)90363-3. [DOI] [PubMed] [Google Scholar]
  16. Mizrahi J., Escher E., D'Orléans-Juste P., Regoli D. Undeca- and octa-peptide antagonists for substance P, a study on the guinea pig trachea. Eur J Pharmacol. 1984 Mar 23;99(2-3):193–202. doi: 10.1016/0014-2999(84)90241-3. [DOI] [PubMed] [Google Scholar]
  17. Morimoto H., Fujii T., Senoh H. Plasma extravasation by chemical mediators in rat skin and trachea: a role of neurogenic agents on tracheal edema formation. Jpn J Pharmacol. 1989 Mar;49(3):389–395. doi: 10.1254/jjp.49.389. [DOI] [PubMed] [Google Scholar]
  18. Norman P., Abram T. S., Kluender H. C., Gardiner P. J., Cuthbert N. J. The binding of [3H]leukotriene C4 to guinea-pig lung membranes. The lack of correlation of LTC4 functional activity with binding affinity. Eur J Pharmacol. 1987 Nov 17;143(3):323–334. doi: 10.1016/0014-2999(87)90456-0. [DOI] [PubMed] [Google Scholar]
  19. Pernow B. Substance P. Pharmacol Rev. 1983 Jun;35(2):85–141. [PubMed] [Google Scholar]
  20. Regoli D., Drapeau G., Dion S., Couture R. New selective agonists for neurokinin receptors: pharmacological tools for receptor characterization. Trends Pharmacol Sci. 1988 Aug;9(8):290–295. doi: 10.1016/0165-6147(88)90013-2. [DOI] [PubMed] [Google Scholar]
  21. Snider R. M., Constantine J. W., Lowe J. A., 3rd, Longo K. P., Lebel W. S., Woody H. A., Drozda S. E., Desai M. C., Vinick F. J., Spencer R. W. A potent nonpeptide antagonist of the substance P (NK1) receptor. Science. 1991 Jan 25;251(4992):435–437. doi: 10.1126/science.1703323. [DOI] [PubMed] [Google Scholar]
  22. Zukin S. R., Young A. B., Snyder S. H. Gamma-aminobutyric acid binding to receptor sites in the rat central nervous system. Proc Natl Acad Sci U S A. 1974 Dec;71(12):4802–4807. doi: 10.1073/pnas.71.12.4802. [DOI] [PMC free article] [PubMed] [Google Scholar]

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