Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Sep 26;92(20):9067–9071. doi: 10.1073/pnas.92.20.9067

High-affinity neuropeptide Y receptor antagonists.

A J Daniels 1, J E Matthews 1, R J Slepetis 1, M Jansen 1, O H Viveros 1, A Tadepalli 1, W Harrington 1, D Heyer 1, A Landavazo 1, J J Leban 1, et al.
PMCID: PMC40925  PMID: 7568074

Abstract

Neuropeptide Y (NPY) is one of the most abundant peptide transmitters in the mammalian brain. In the periphery it is costored and coreleased with norepinephrine from sympathetic nerve terminals. However, the physiological functions of this peptide remain unclear because of the absence of specific high-affinity receptor antagonists. Three potent NPY receptor antagonists were synthesized and tested for their biological activity in in vitro, ex vivo, and in vivo functional assays. We describe here the effects of these antagonists inhibiting specific radiolabeled NPY binding at Y1 and Y2 receptors and antagonizing the effects of NPY in human erythroleukemia cell intracellular calcium mobilization perfusion pressure in the isolated rat kidney, and mean arterial blood pressure in anesthetized rats.

Full text

PDF
9067

Selected References

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

  1. Adrian T. E., Allen J. M., Bloom S. R., Ghatei M. A., Rossor M. N., Roberts G. W., Crow T. J., Tatemoto K., Polak J. M. Neuropeptide Y distribution in human brain. Nature. 1983 Dec 8;306(5943):584–586. doi: 10.1038/306584a0. [DOI] [PubMed] [Google Scholar]
  2. Balasubramaniam A., Sheriff S., Johnson M. E., Prabhakaran M., Huang Y., Fischer J. E., Chance W. T. [D-TRP32]neuropeptide Y: a competitive antagonist of NPY in rat hypothalamus. J Med Chem. 1994 Mar 18;37(6):811–815. doi: 10.1021/jm00032a015. [DOI] [PubMed] [Google Scholar]
  3. Beck-Sickinger A. G., Jung G. Structure-activity relationships of neuropeptide Y analogues with respect to Y1 and Y2 receptors. Biopolymers. 1995;37(2):123–142. doi: 10.1002/bip.360370207. [DOI] [PubMed] [Google Scholar]
  4. Chaurasia C., Misse G., Tessel R., Doughty M. B. Nonpeptide peptidomimetic antagonists of the neuropeptide Y receptor: benextramine analogs with selectivity for the peripheral Y2 receptor. J Med Chem. 1994 Jul 8;37(14):2242–2248. doi: 10.1021/jm00040a018. [DOI] [PubMed] [Google Scholar]
  5. Daniels A. J., Lazarowski E. R., Matthews J. E., Lapetina E. G. Neuropeptide Y mobilizes intracellular Ca2+ and increases inositol phosphate production in human erythroleukemia cells. Biochem Biophys Res Commun. 1989 Dec 29;165(3):1138–1144. doi: 10.1016/0006-291x(89)92721-6. [DOI] [PubMed] [Google Scholar]
  6. Daniels A. J., Matthews J. E., Humberto Viveros O., Lazarowski E. R. Characterization of the neuropeptide Y-induced intracellular calcium release in human erythroleukemic cells. Mol Pharmacol. 1992 Apr;41(4):767–771. [PubMed] [Google Scholar]
  7. Doughty M. B., Chaurasia C. S., Li K. Benextramine-neuropeptide Y receptor interactions: contribution of the benzylic moieties to [3H]neuropeptide Y displacement activity. J Med Chem. 1993 Jan 22;36(2):272–279. doi: 10.1021/jm00054a012. [DOI] [PubMed] [Google Scholar]
  8. Fuhlendorff J., Gether U., Aakerlund L., Langeland-Johansen N., Thøgersen H., Melberg S. G., Olsen U. B., Thastrup O., Schwartz T. W. [Leu31, Pro34]neuropeptide Y: a specific Y1 receptor agonist. Proc Natl Acad Sci U S A. 1990 Jan;87(1):182–186. doi: 10.1073/pnas.87.1.182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Glowa J. R., Insel T. R. Effects of chlordiazepoxide and beta-carboline 3-carboxylic acid ethyl ester on non-suppressed and minimally-suppressed responding in the squirrel monkey. Life Sci. 1992;50(1):7–14. doi: 10.1016/0024-3205(92)90191-q. [DOI] [PubMed] [Google Scholar]
  10. Gordon E. A., Kohout T. A., Fishman P. H. Characterization of functional neuropeptide Y receptors in a human neuroblastoma cell line. J Neurochem. 1990 Aug;55(2):506–513. doi: 10.1111/j.1471-4159.1990.tb04164.x. [DOI] [PubMed] [Google Scholar]
  11. Gray T. S., Morley J. E. Neuropeptide Y: anatomical distribution and possible function in mammalian nervous system. Life Sci. 1986 Feb 3;38(5):389–401. doi: 10.1016/0024-3205(86)90061-5. [DOI] [PubMed] [Google Scholar]
  12. Lambert P. D., Wilding J. P., al-Dokhayel A. A., Bohuon C., Comoy E., Gilbey S. G., Bloom S. R. A role for neuropeptide-Y, dynorphin, and noradrenaline in the central control of food intake after food deprivation. Endocrinology. 1993 Jul;133(1):29–32. doi: 10.1210/endo.133.1.8100519. [DOI] [PubMed] [Google Scholar]
  13. Leban J. J., Heyer D., Landavazo A., Matthews J., Aulabaugh A., Daniels A. J. Novel modified carboxy terminal fragments of neuropeptide Y with high affinity for Y2-type receptors and potent functional antagonism at a Y1-type receptor. J Med Chem. 1995 Mar 31;38(7):1150–1157. doi: 10.1021/jm00007a012. [DOI] [PubMed] [Google Scholar]
  14. Lundberg J. M., Terenius L., Hökfelt T., Tatemoto K. Comparative immunohistochemical and biochemical analysis of pancreatic polypeptide-like peptides with special reference to presence of neuropeptide Y in central and peripheral neurons. J Neurosci. 1984 Sep;4(9):2376–2386. doi: 10.1523/JNEUROSCI.04-09-02376.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Michel M. C. Receptors for neuropeptide Y: multiple subtypes and multiple second messengers. Trends Pharmacol Sci. 1991 Oct;12(10):389–394. doi: 10.1016/0165-6147(91)90610-5. [DOI] [PubMed] [Google Scholar]
  16. Rudolf K., Eberlein W., Engel W., Wieland H. A., Willim K. D., Entzeroth M., Wienen W., Beck-Sickinger A. G., Doods H. N. The first highly potent and selective non-peptide neuropeptide Y Y1 receptor antagonist: BIBP3226. Eur J Pharmacol. 1994 Dec 27;271(2-3):R11–R13. doi: 10.1016/0014-2999(94)90822-2. [DOI] [PubMed] [Google Scholar]
  17. Stanley B. G., Magdalin W., Seirafi A., Nguyen M. M., Leibowitz S. F. Evidence for neuropeptide Y mediation of eating produced by food deprivation and for a variant of the Y1 receptor mediating this peptide's effect. Peptides. 1992 May-Jun;13(3):581–587. doi: 10.1016/0196-9781(92)90093-i. [DOI] [PubMed] [Google Scholar]
  18. Tatemoto K., Carlquist M., Mutt V. Neuropeptide Y--a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide. Nature. 1982 Apr 15;296(5858):659–660. doi: 10.1038/296659a0. [DOI] [PubMed] [Google Scholar]
  19. Tatemoto K., Mann M. J., Shimizu M. Synthesis of receptor antagonists of neuropeptide Y. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1174–1178. doi: 10.1073/pnas.89.4.1174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Wahlestedt C., Pich E. M., Koob G. F., Yee F., Heilig M. Modulation of anxiety and neuropeptide Y-Y1 receptors by antisense oligodeoxynucleotides. Science. 1993 Jan 22;259(5094):528–531. doi: 10.1126/science.8380941. [DOI] [PubMed] [Google Scholar]
  21. Wahlestedt C., Reis D. J. Neuropeptide Y-related peptides and their receptors--are the receptors potential therapeutic drug targets? Annu Rev Pharmacol Toxicol. 1993;33:309–352. doi: 10.1146/annurev.pa.33.040193.001521. [DOI] [PubMed] [Google Scholar]
  22. Wahlestedt C., Yanaihara N., Håkanson R. Evidence for different pre-and post-junctional receptors for neuropeptide Y and related peptides. Regul Pept. 1986 Feb;13(3-4):307–318. doi: 10.1016/0167-0115(86)90048-0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES