Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1991 Oct;104(2):355–360. doi: 10.1111/j.1476-5381.1991.tb12435.x

Pharmacological specificity of novel, synthetic, cyclic peptides as antagonists at tachykinin receptors.

A T McKnight 1, J J Maguire 1, N J Elliott 1, A E Fletcher 1, A C Foster 1, R Tridgett 1, B J Williams 1, J Longmore 1, L L Iversen 1
PMCID: PMC1908569  PMID: 1665732

Abstract

1. The interaction at tachykinin receptors of a series of novel cyclic hexapeptides has been examined by use of radioligand binding assays (NK1 and NK3 sites in rat cortex, NK2 sites in hamster urinary bladder) and functional pharmacological assays (guinea-pig ileum, rat vas deferens and rat portal vein for NK1, NK2 and NK3 receptors, respectively). 2. The compounds cyclo(GlnTrpPhe(R)Gly[ANC-2]LeuMet) (L-659,837) and cyclo(GlnTrpPheGly-LeuMet) (L-659,877) were powerful and selective displacers of NK2 binding (pIC50 6.9 and 8.0, respectively), and were competitive antagonists of responses to stimulation of NK2 receptors in rat vas deferens (pKB for antagonism of responses to eledoisin 6.7 and 8.1, respectively). Responses in the NK1 and NK3 pharmacological assays were blocked only weakly, if at all. 3. In the longitudinal muscle of the small intestine of the rat, responses to stimulation of the putative NK2 receptor by eledoisin, neurokinin A or neurokinin B were antagonized by both cyclo(GlnTrpPhe(R)-Gly[ANC-2]LeuMet) and cyclo (GlnTrpPheGlyLeuMet) in a manner consistent with the presence in this tissue of a uniform population of receptors, indistinguishable from the NK2 receptor of the rat vas deferens. 4. The compounds cyclo(GlnTrpPheGlyLeuMet) and the lactam-containing analogue are among the most selective antagonists for the NK2 receptor that have been described; their availability should be of value in the characterization of the receptors mediating responses to tachykinins, and in elucidating the physiological functions of the tachykinin receptors.

Full text

PDF
355

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  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. Bristow D. R., Curtis N. R., Suman-Chauhan N., Watling K. J., Williams B. J. Effects of tachykinins on inositol phospholipid hydrolysis in slices of hamster urinary bladder. Br J Pharmacol. 1987 Jan;90(1):211–217. doi: 10.1111/j.1476-5381.1987.tb16842.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cascieri M. A., Chicchi G. G., Freidinger R. M., Colton C. D., Perlow D. S., Williams B., Curtis N. R., McKnight A. T., Maguire J. J., Veber D. F. Conformationally constrained tachykinin analogs which are selective ligands for the eledoisin binding site. Mol Pharmacol. 1986 Jan;29(1):34–38. [PubMed] [Google Scholar]
  4. Cascieri M. A., Goldenberg M. M., Liang T. Biological activity of substance P methyl ester. Mol Pharmacol. 1981 Nov;20(3):457–459. [PubMed] [Google Scholar]
  5. Corbett A. D., McKnight A. T., Kosterlitz H. W. Tetraethylammonium facilitates the stimulation-evoked loss of the enkephalins from the myenteric plexus of guinea-pig ileum. Proc R Soc Lond B Biol Sci. 1981 Oct 14;213(1191):171–182. doi: 10.1098/rspb.1981.0060. [DOI] [PubMed] [Google Scholar]
  6. DeLean A., Munson P. J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. doi: 10.1152/ajpendo.1978.235.2.E97. [DOI] [PubMed] [Google Scholar]
  7. Erspamer G. F., Erspamer V., Piccinelli D. Parallel bioassay of physalaemin and kassinin, a tachykinin dodecapeptide from the skin of the African frog Kassina senegalensis. Naunyn Schmiedebergs Arch Pharmacol. 1980 Feb;311(1):61–65. doi: 10.1007/BF00500303. [DOI] [PubMed] [Google Scholar]
  8. Foster A. C., Tridgett R. Comparison of the binding of radiolabelled neurokinin A and eledoisin in rat cortex synaptic membranes. Br J Pharmacol. 1988 Jun;94(2):602–608. doi: 10.1111/j.1476-5381.1988.tb11566.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kenakin T. P. The classification of drugs and drug receptors in isolated tissues. Pharmacol Rev. 1984 Sep;36(3):165–222. [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. Laufer R., Wormser U., Friedman Z. Y., Gilon C., Chorev M., Selinger Z. Neurokinin B is a preferred agonist for a neuronal substance P receptor and its action is antagonized by enkephalin. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7444–7448. doi: 10.1073/pnas.82.21.7444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Lee C. M., Iversen L. L., Hanley M. R., Sandberg B. E. The possible existence of multiple receptors for substance P. Naunyn Schmiedebergs Arch Pharmacol. 1982 Mar;318(4):281–287. doi: 10.1007/BF00501166. [DOI] [PubMed] [Google Scholar]
  14. Maggi C. A., Patacchini R., Giuliani S., Rovero P., Dion S., Regoli D., Giachetti A., Meli A. Competitive antagonists discriminate between NK2 tachykinin receptor subtypes. Br J Pharmacol. 1990 Jul;100(3):589–592. doi: 10.1111/j.1476-5381.1990.tb15851.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Masu Y., Nakayama K., Tamaki H., Harada Y., Kuno M., Nakanishi S. cDNA cloning of bovine substance-K receptor through oocyte expression system. 1987 Oct 29-Nov 4Nature. 329(6142):836–838. doi: 10.1038/329836a0. [DOI] [PubMed] [Google Scholar]
  16. McKnight A. T., Corbett A. D., Marcoli M., Kosterlitz H. W. The opioid receptors in the hamster vas deferens are of the delta-type. Neuropharmacology. 1985 Nov;24(11):1011–1017. doi: 10.1016/0028-3908(85)90184-4. [DOI] [PubMed] [Google Scholar]
  17. Regoli D., Drapeau G., Dion S., D'Orléans-Juste P. Pharmacological receptors for substance P and neurokinins. Life Sci. 1987 Jan 12;40(2):109–117. doi: 10.1016/0024-3205(87)90349-3. [DOI] [PubMed] [Google Scholar]
  18. Rovero P., Pestellini V., Maggi C. A., Patacchini R., Regoli D., Giachetti A. A highly selective NK-2 tachykinin receptor antagonist containing D-tryptophan. Eur J Pharmacol. 1990 Jan 3;175(1):113–115. doi: 10.1016/0014-2999(90)90161-x. [DOI] [PubMed] [Google Scholar]
  19. Shigemoto R., Yokota Y., Tsuchida K., Nakanishi S. Cloning and expression of a rat neuromedin K receptor cDNA. J Biol Chem. 1990 Jan 15;265(2):623–628. [PubMed] [Google Scholar]
  20. 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]
  21. Viger A., Beaujouan J. C., Torrens Y., Glowinski J. Specific binding of a 125I-substance P derivative to rat brain synaptosomes. J Neurochem. 1983 Apr;40(4):1030–1039. doi: 10.1111/j.1471-4159.1983.tb08089.x. [DOI] [PubMed] [Google Scholar]
  22. Ward P., Ewan G. B., Jordan C. C., Ireland S. J., Hagan R. M., Brown J. R. Potent and highly selective neurokinin antagonists. J Med Chem. 1990 Jul;33(7):1848–1851. doi: 10.1021/jm00169a003. [DOI] [PubMed] [Google Scholar]
  23. Watson S. P. Are the proposed substance P receptor sub-types, substance P receptors? Life Sci. 1984 Aug 20;35(8):797–808. doi: 10.1016/0024-3205(84)90403-x. [DOI] [PubMed] [Google Scholar]
  24. Watson S. P., Sandberg B. E., Hanley M. R., Iversen L. L. Tissue selectivity of substance P alkyl esters: suggesting multiple receptors. Eur J Pharmacol. 1983 Jan 28;87(1):77–84. doi: 10.1016/0014-2999(83)90052-3. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES