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. 1991 Feb;102(2):511–517. doi: 10.1111/j.1476-5381.1991.tb12202.x

Novel selective agonists and antagonists confirm neurokinin NK1 receptors in guinea-pig vas deferens.

J M Hall 1, I K Morton 1
PMCID: PMC1918041  PMID: 1707714

Abstract

1. This study investigated the recognition characteristics of neurokinin receptors mediating potentiation of the contractile response to field stimulation in the guinea-pig vas deferens. 2. A predominant NK1 receptor population is strongly suggested by the relative activities of the common naturally-occurring tachykinin agonists, which fall within less than one order of magnitude. This conclusion is supported by the relative activities of the synthetic NK1 selective agonists substance P methyl ester, [Glp6,L-Pro9]-SP(6-11) and delta-aminovaleryl-[L-Pro9,N-MeLeu10]- SP(7-11) (GR73632) which were 0.78, 9.3 and 120 as active as substance P, respectively. Furthermore, the NK2 selective agonist [Lys3, Gly8,-R-gamma-lactam-Leu9]-NKA(3-10) (GR64349) was active only at the highest concentrations tested (greater than 10 microM), and the NK3 selective agonist, succ-[Asp6,N-MePhe8]-SP(6-11) (senktide) was essentially inactive (10 nM-32 microM). 3. [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-SP(1-11) antagonized responses to neurokinin A, neurokinin B, physalaemin, eledoisin, [Glp6,D-Pro9]-SP(6-11), GR73632 and GR64349 (apparent pKB s 5.6-6.2), but was less potent in antagonizing responses to substance P, substance P methyl ester and [Glp6,L-Pro9]-SP(6-11) (apparent pKB s less than or equal to 5.0-5.0). 4. In contrast, the recently developed NK1-selective receptor antagonist [D-Pro9[Spiro-gamma-lactam]Leu10,Trp11]-SP(1-11) (GR71251) did not produce agonist-dependent pKB estimates. Schild plot analysis indicated a competitive interaction with a single receptor population where the antagonist had an estimated overall pKB of 7.58 +/- 0.13 for the four agonists of differing subtype selectivity tested (GR73632, GR64349, substance P methyl ester and neurokinin B).(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Bailey S. J., Featherstone R. L., Jordan C. C., Morton I. K. An examination of the pharmacology of two substance P antagonists and the evidence for tachykinin receptor subtypes. Br J Pharmacol. 1986 Jan;87(1):79–85. doi: 10.1111/j.1476-5381.1986.tb10159.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., Goldenberg M. M., Liang T. Biological activity of substance P methyl ester. Mol Pharmacol. 1981 Nov;20(3):457–459. [PubMed] [Google Scholar]
  4. Demolle D., Boeynaems J. M. Cholera and pertussis toxins amplify prostacyclin synthesis in aortic smooth muscle cells. Br J Pharmacol. 1989 Nov;98(3):717–720. doi: 10.1111/j.1476-5381.1989.tb14597.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dolezal V., Tucek S. Failure of the calcium channel activator, Bay K 8644, to increase the release of acetylcholine from nerve terminals in brain and diaphragm. Br J Pharmacol. 1987 Jul;91(3):475–479. doi: 10.1111/j.1476-5381.1987.tb11239.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Drapeau G., D'Orléans-Juste P., Dion S., Rhaleb N. E., Rouissi N. E., Regoli D. Selective agonists for substance P and neurokinin receptors. Neuropeptides. 1987 Jul;10(1):43–54. doi: 10.1016/0143-4179(87)90088-6. [DOI] [PubMed] [Google Scholar]
  7. Ellis J. L., Burnstock G. Modulation of neurotransmission in the guinea-pig vas deferens by capsaicin: involvement of calcitonin gene-related peptide and substance P. Br J Pharmacol. 1989 Oct;98(2):707–713. doi: 10.1111/j.1476-5381.1989.tb12646.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Folkers K., Håkanson R., Hörig J., Xu J. C., Leander S. Biological evaluation of substance P antagonists. Br J Pharmacol. 1984 Oct;83(2):449–456. doi: 10.1111/j.1476-5381.1984.tb16506.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hall J. M., Fox A. J., Morton I. K. Peptidase activity as a determinant of agonist potencies in some smooth muscle preparations. Eur J Pharmacol. 1990 Feb 6;176(2):127–134. doi: 10.1016/0014-2999(90)90520-g. [DOI] [PubMed] [Google Scholar]
  10. Jensen R. T., Jones S. W., Folkers K., Gardner J. D. A synthetic peptide that is a bombesin receptor antagonist. Nature. 1984 May 3;309(5963):61–63. doi: 10.1038/309061a0. [DOI] [PubMed] [Google Scholar]
  11. Laufer R., Gilon C., Chorev M., Selinger Z. Characterization of a neurokinin B receptor site in rat brain using a highly selective radioligand. J Biol Chem. 1986 Aug 5;261(22):10257–10263. [PubMed] [Google Scholar]
  12. Laufer R., Gilon C., Chorev M., Selinger Z. [pGlu6,Pro9]SP6-11, a selective agonist for the substance P P-receptor subtype. J Med Chem. 1986 Jul;29(7):1284–1288. doi: 10.1021/jm00157a029. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. Lembeck F., Amann R., Barthó L. Studies on effects of the substance P analogues [D-Pro2, D-Trp7,9]-substance P and [D-Arg1, D-Trp7,9, L-Leu11]-substance P not related to their antagonist action. Naunyn Schmiedebergs Arch Pharmacol. 1986 Jul;333(3):290–293. doi: 10.1007/BF00512943. [DOI] [PubMed] [Google Scholar]
  16. Mizrahi J., Dion S., D'Orléans-Juste P., Regoli D. Activities and antagonism of bombesin on urinary smooth muscles. Eur J Pharmacol. 1985 May 20;111(3):339–345. doi: 10.1016/0014-2999(85)90640-5. [DOI] [PubMed] [Google Scholar]
  17. Mussap C. J., Lew R., Burcher E. The autoradiographic distribution of substance P binding sites in guinea-pig vas deferens is altered by capsaicin pretreatment. Eur J Pharmacol. 1989 Sep 22;168(3):337–345. doi: 10.1016/0014-2999(89)90795-4. [DOI] [PubMed] [Google Scholar]
  18. Piercey M. F., Dobry-Schreur P. J., Masiques N., Schroeder L. A. Stereospecificity of SP1 and SP2 substance P receptors. Life Sci. 1985 Feb 25;36(8):777–780. doi: 10.1016/0024-3205(85)90198-5. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Rovero P., Pestellini V., Patacchini R., Giuliani S., Santicioli P., Maggi C. A., Meli A., Giachetti A. A potent and selective agonist for NK-2 tachykinin receptor. Peptides. 1989 May-Jun;10(3):593–595. doi: 10.1016/0196-9781(89)90148-4. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. 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]
  23. Watson S. P. Pharmacological characterization of a substance P antagonist, [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-substance P. Br J Pharmacol. 1983 Sep;80(1):205–209. doi: 10.1111/j.1476-5381.1983.tb11067.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Watson S. P. Rapid degradation of [3H]-substance p in guinea-pig ileum and rat vas deferens in vitro. Br J Pharmacol. 1983 Jun;79(2):543–552. doi: 10.1111/j.1476-5381.1983.tb11029.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Wormser U., Laufer R., Hart Y., Chorev M., Gilon C., Selinger Z. Highly selective agonists for substance P receptor subtypes. EMBO J. 1986 Nov;5(11):2805–2808. doi: 10.1002/j.1460-2075.1986.tb04571.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Yachnis A. T., Crawley J. N., Jensen R. T., McGrane M. M., Moody T. W. The antagonism of bombesin in the CNS by substance P analogues. Life Sci. 1984 Nov 5;35(19):1963–1969. doi: 10.1016/0024-3205(84)90477-6. [DOI] [PubMed] [Google Scholar]
  28. von Euler U. S., Hedqvist P. Phenoxybenzamine blockade of the enhancing effect of substance P on the twitch induced by transmural nerve stimulation in the guinea pig vas deferens. Acta Physiol Scand. 1974 Oct;92(2):283–285. doi: 10.1111/j.1748-1716.1974.tb05746.x. [DOI] [PubMed] [Google Scholar]

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