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. 1996 Nov;119(5):851–854. doi: 10.1111/j.1476-5381.1996.tb15750.x

The effects of (RS)-alpha-cyclopropyl-4-phosphonophenylglycine ((RS)-CPPG), a potent and selective metabotropic glutamate receptor antagonist.

N J Toms 1, D E Jane 1, M C Kemp 1, J S Bedingfield 1, P J Roberts 1
PMCID: PMC1915959  PMID: 8922731

Abstract

1. In this study we describe the potent antagonist activity of a novel metabotropic glutamate (mGlu) receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine ((RS)-CPPG) which exhibits selectivity for mGlu receptors (group II and III) negatively coupled to adenylyl cyclase in the adult rat cortex. 2. Both the L-2-amino-4-phosphonobutyrate (L-AP4) and (2S, 1'S, 2'S)-2-(carboxycyclopropyl)glycine (L-CCG-1) inhibition of forskolin-stimulated cyclic AMP accumulation were potently reversed by (RS)-CPPG (IC50 values: 2.2 +/- 0.6 nM and 46.2 +/- 18.2 nM, respectively). 3. In contrast, (RS)-CPPG acted as a weak antagonist against group I mGlu receptors. In neonatal rat cortical slices, (RS)-CPPG antagonized (KB = 0.65 +/- 0.07 mM) (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD)-stimulated phosphoinositide hydrolysis. (RS)-CPPG (100 microM) failed to influence L-quisqualate-stimulated phosphoinositide hydrolysis in cultured cerebellar granule cells. 4. In the rat cerebral cortex, (RS)-CPPG is the most potent antagonist of group II/III mGlu receptors yet described (with 20 fold selectivity for group III mGlu receptors), having negligible activity at group I mGlu receptors.

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Selected References

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  1. Abe T., Sugihara H., Nawa H., Shigemoto R., Mizuno N., Nakanishi S. Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca2+ signal transduction. J Biol Chem. 1992 Jul 5;267(19):13361–13368. [PubMed] [Google Scholar]
  2. Aramori I., Nakanishi S. Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGluR1, in transfected CHO cells. Neuron. 1992 Apr;8(4):757–765. doi: 10.1016/0896-6273(92)90096-v. [DOI] [PubMed] [Google Scholar]
  3. Bedingfield J. S., Jane D. E., Kemp M. C., Toms N. J., Roberts P. J. Novel potent selective phenylglycine antagonists of metabotropic glutamate receptors. Eur J Pharmacol. 1996 Aug 1;309(1):71–78. doi: 10.1016/0014-2999(96)00313-5. [DOI] [PubMed] [Google Scholar]
  4. Berridge M. J., Downes C. P., Hanley M. R. Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands. Biochem J. 1982 Sep 15;206(3):587–595. doi: 10.1042/bj2060587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Birse E. F., Eaton S. A., Jane D. E., Jones P. L., Porter R. H., Pook P. C., Sunter D. C., Udvarhelyi P. M., Wharton B., Roberts P. J. Phenylglycine derivatives as new pharmacological tools for investigating the role of metabotropic glutamate receptors in the central nervous system. Neuroscience. 1993 Feb;52(3):481–488. doi: 10.1016/0306-4522(93)90400-a. [DOI] [PubMed] [Google Scholar]
  6. Brabet I., Mary S., Bockaert J., Pin J. P. Phenylglycine derivatives discriminate between mGluR1- and mGluR5-mediated responses. Neuropharmacology. 1995 Aug;34(8):895–903. doi: 10.1016/0028-3908(95)00079-l. [DOI] [PubMed] [Google Scholar]
  7. Brown B. L., Ekins R. P., Albano J. D. Saturation assay for cyclic AMP using endogenous binding protein. Adv Cyclic Nucleotide Res. 1972;2:25–40. [PubMed] [Google Scholar]
  8. Catania M. V., Landwehrmeyer G. B., Testa C. M., Standaert D. G., Penney J. B., Jr, Young A. B. Metabotropic glutamate receptors are differentially regulated during development. Neuroscience. 1994 Aug;61(3):481–495. doi: 10.1016/0306-4522(94)90428-6. [DOI] [PubMed] [Google Scholar]
  9. Duvoisin R. M., Zhang C., Ramonell K. A novel metabotropic glutamate receptor expressed in the retina and olfactory bulb. J Neurosci. 1995 Apr;15(4):3075–3083. doi: 10.1523/JNEUROSCI.15-04-03075.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Eaton S. A., Jane D. E., Jones P. L., Porter R. H., Pook P. C., Sunter D. C., Udvarhelyi P. M., Roberts P. J., Salt T. E., Watkins J. C. Competitive antagonism at metabotropic glutamate receptors by (S)-4-carboxyphenylglycine and (RS)-alpha-methyl-4-carboxyphenylglycine. Eur J Pharmacol. 1993 Jan 15;244(2):195–197. doi: 10.1016/0922-4106(93)90028-8. [DOI] [PubMed] [Google Scholar]
  11. Kemp M., Roberts P., Pook P., Jane D., Jones A., Jones P., Sunter D., Udvarhelyi P., Watkins J. Antagonism of presynaptically mediated depressant responses and cyclic AMP-coupled metabotropic glutamate receptors. Eur J Pharmacol. 1994 Jan 15;266(2):187–192. doi: 10.1016/0922-4106(94)90109-0. [DOI] [PubMed] [Google Scholar]
  12. Monaghan D. T., Bridges R. J., Cotman C. W. The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system. Annu Rev Pharmacol Toxicol. 1989;29:365–402. doi: 10.1146/annurev.pa.29.040189.002053. [DOI] [PubMed] [Google Scholar]
  13. Nakajima Y., Iwakabe H., Akazawa C., Nawa H., Shigemoto R., Mizuno N., Nakanishi S. Molecular characterization of a novel retinal metabotropic glutamate receptor mGluR6 with a high agonist selectivity for L-2-amino-4-phosphonobutyrate. J Biol Chem. 1993 Jun 5;268(16):11868–11873. [PubMed] [Google Scholar]
  14. Ohishi H., Shigemoto R., Nakanishi S., Mizuno N. Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain: an in situ hybridization study. J Comp Neurol. 1993 Sep 8;335(2):252–266. doi: 10.1002/cne.903350209. [DOI] [PubMed] [Google Scholar]
  15. Okamoto N., Hori S., Akazawa C., Hayashi Y., Shigemoto R., Mizuno N., Nakanishi S. Molecular characterization of a new metabotropic glutamate receptor mGluR7 coupled to inhibitory cyclic AMP signal transduction. J Biol Chem. 1994 Jan 14;269(2):1231–1236. [PubMed] [Google Scholar]
  16. Pin J. P., Duvoisin R. The metabotropic glutamate receptors: structure and functions. Neuropharmacology. 1995 Jan;34(1):1–26. doi: 10.1016/0028-3908(94)00129-g. [DOI] [PubMed] [Google Scholar]
  17. Porter R. H., Roberts P. J., Jane D. E., Watkins J. C. (S)-homoquisqualate: a potent agonist at the glutamate metabotropic receptor. Br J Pharmacol. 1992 Jul;106(3):509–510. doi: 10.1111/j.1476-5381.1992.tb14366.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Roberts P. J. Pharmacological tools for the investigation of metabotropic glutamate receptors (mGluRs): phenylglycine derivatives and other selective antagonists--an update. Neuropharmacology. 1995 Aug;34(8):813–819. doi: 10.1016/0028-3908(95)00094-m. [DOI] [PubMed] [Google Scholar]
  19. Santi M. R., Ikonomovic S., Wroblewski J. T., Grayson D. R. Temporal and depolarization-induced changes in the absolute amounts of mRNAs encoding metabotropic glutamate receptors in cerebellar granule neurons in vitro. J Neurochem. 1994 Oct;63(4):1207–1217. doi: 10.1046/j.1471-4159.1994.63041207.x. [DOI] [PubMed] [Google Scholar]
  20. Saugstad J. A., Kinzie J. M., Mulvihill E. R., Segerson T. P., Westbrook G. L. Cloning and expression of a new member of the L-2-amino-4-phosphonobutyric acid-sensitive class of metabotropic glutamate receptors. Mol Pharmacol. 1994 Mar;45(3):367–372. [PubMed] [Google Scholar]
  21. Shigemoto R., Nomura S., Ohishi H., Sugihara H., Nakanishi S., Mizuno N. Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain. Neurosci Lett. 1993 Nov 26;163(1):53–57. doi: 10.1016/0304-3940(93)90227-c. [DOI] [PubMed] [Google Scholar]
  22. Tanabe Y., Masu M., Ishii T., Shigemoto R., Nakanishi S. A family of metabotropic glutamate receptors. Neuron. 1992 Jan;8(1):169–179. doi: 10.1016/0896-6273(92)90118-w. [DOI] [PubMed] [Google Scholar]
  23. Tanabe Y., Nomura A., Masu M., Shigemoto R., Mizuno N., Nakanishi S. Signal transduction, pharmacological properties, and expression patterns of two rat metabotropic glutamate receptors, mGluR3 and mGluR4. J Neurosci. 1993 Apr;13(4):1372–1378. doi: 10.1523/JNEUROSCI.13-04-01372.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Toms N. J., Jane D. E., Tse H. W., Roberts P. J. Characterization of metabotropic glutamate receptor-stimulated phosphoinositide hydrolysis in rat cultured cerebellar granule cells. Br J Pharmacol. 1995 Dec;116(7):2824–2827. doi: 10.1111/j.1476-5381.1995.tb15932.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Voss T., Wallner E. An easy cAMP extraction method facilitating adenylyl cyclase assays. Anal Biochem. 1992 Nov 15;207(1):40–43. doi: 10.1016/0003-2697(92)90496-t. [DOI] [PubMed] [Google Scholar]
  26. Watkins J., Collingridge G. Phenylglycine derivatives as antagonists of metabotropic glutamate receptors. Trends Pharmacol Sci. 1994 Sep;15(9):333–342. doi: 10.1016/0165-6147(94)90028-0. [DOI] [PubMed] [Google Scholar]

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