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. 1995 Dec;116(8):3323–3329. doi: 10.1111/j.1476-5381.1995.tb15142.x

Structure-activity relationships for a series of phenylglycine derivatives acting at metabotropic glutamate receptors (mGluRs).

J S Bedingfield 1, M C Kemp 1, D E Jane 1, H W Tse 1, P J Roberts 1, J C Watkins 1
PMCID: PMC1909163  PMID: 8719814

Abstract

1. The actions of a series of twelve phenylglycine derivatives at metabotropic glutamate receptors (mGluRs) linked to both phosphoinositide hydrolysis (PI) and cyclic AMP were investigated. 2. PI hydrolysis was determined by the accumulation of [3H]-inositol-monophosphate ([3H]-IP1) in neonatal ral cortical slices prelabelled with [3H]-myo-inositol. The non-selective mGluR agonist (1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid ((1S,3R)-ACPD) produced a concentration-dependent increase in [3H]-IP1 (EC50 approximately 20 microM). This agonist was subsequently used to investigate potential antagonist activity of the phenylglycine derivatives. Of the compounds tested (+)-alpha-methyl-4-carboxyphenylglycine (M4CPG) and (RS)-alpha-ethyl-4-carboxyphenylglycine (E4CPG) were the most active with KP values of 0.184 +/- 0.04 mM and 0.367 +/- 0.2 mM respectively. 3. Activity at adenylyl cylase-coupled mGluRs was investigated by determining the accumulation of [3H]-cyclic AMP in adult rat cortical slices. [3H]-cyclic AMP accumulation, elicited by 30 microM forskolin, was inhibited by (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-1) and L-2-amino-4-phosphonobutanoate (L-AP4) with respective EC50 values of 0.3 microM and 10 microM. Neither agonist was able to inhibit completely forskolin stimulated cyclic AMP accumulation; this is evidence that not all adenylyl cyclase is susceptible to modulation by mGluRs. Phenylglycine derivatives were examined for their ability to antagonize the inhibition of [3H]-cyclic AMP accumulation by L-CCG-1 or L-AP4 at their EC50 concentrations. 4. A rank order of potency of the phenylglycine derivatives as antagonists of L-AP4 and L-CCG-1 was obtained. The most effective compound. (RS)-alpha-methyl-3-carboxymethylphenylglycine (M3CMPG) had IC50 values in the order of 1 microM against L-AP4 and 0.4 microM against L-CCG-1. 5. The results from this study indicate that phenylglycine-derived compounds can discriminate between groups of metabotropic glutamate receptors and may also display some selective activity between subtypes within groups. Future work based on these findings may lead to the development of more selective and potent compounds as important pharmacological tools.

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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. Allan R. D., Hanrahan J. R., Hambley T. W., Johnston G. A., Mewett K. N., Mitrovic A. D. Synthesis and activity of a potent N-methyl-D-aspartic acid agonist, trans-1-aminocyclobutane-1,3-dicarboxylic acid, and related phosphonic and carboxylic acids. J Med Chem. 1990 Oct;33(10):2905–2915. doi: 10.1021/jm00172a036. [DOI] [PubMed] [Google Scholar]
  3. Baskys A., Malenka R. C. Agonists at metabotropic glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus. J Physiol. 1991 Dec;444:687–701. doi: 10.1113/jphysiol.1991.sp018901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brown E. M., Gamba G., Riccardi D., Lombardi M., Butters R., Kifor O., Sun A., Hediger M. A., Lytton J., Hebert S. C. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature. 1993 Dec 9;366(6455):575–580. doi: 10.1038/366575a0. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. 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]
  7. Forsythe I. D., Clements J. D. Presynaptic glutamate receptors depress excitatory monosynaptic transmission between mouse hippocampal neurones. J Physiol. 1990 Oct;429:1–16. doi: 10.1113/jphysiol.1990.sp018240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hayashi Y., Sekiyama N., Nakanishi S., Jane D. E., Sunter D. C., Birse E. F., Udvarhelyi P. M., Watkins J. C. Analysis of agonist and antagonist activities of phenylglycine derivatives for different cloned metabotropic glutamate receptor subtypes. J Neurosci. 1994 May;14(5 Pt 2):3370–3377. doi: 10.1523/JNEUROSCI.14-05-03370.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Houamed K. M., Kuijper J. L., Gilbert T. L., Haldeman B. A., O'Hara P. J., Mulvihill E. R., Almers W., Hagen F. S. Cloning, expression, and gene structure of a G protein-coupled glutamate receptor from rat brain. Science. 1991 May 31;252(5010):1318–1321. doi: 10.1126/science.1656524. [DOI] [PubMed] [Google Scholar]
  10. Jane D. E., Jones P. L., Pook P. C., Salt T. E., Sunter D. C., Watkins J. C. Stereospecific antagonism by (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) of (1S,3R)-ACPD-induced effects in neonatal rat motoneurones and rat thalamic neurones. Neuropharmacology. 1993 Jul;32(7):725–727. doi: 10.1016/0028-3908(93)90088-k. [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. Kingston A. E., Burnett J. P., Mayne N. G., Lodge D. Pharmacological analysis of 4-carboxyphenylglycine derivatives: comparison of effects on mGluR1 alpha and mGluR5a subtypes. Neuropharmacology. 1995 Aug;34(8):887–894. doi: 10.1016/0028-3908(95)00069-i. [DOI] [PubMed] [Google Scholar]
  13. Masu M., Nakajima Y., Moriyoshi K., Ishii T., Akazawa C., Nakanashi S. Molecular characterization of NMDA and metabotropic glutamate receptors. Ann N Y Acad Sci. 1993 Dec 20;707:153–164. doi: 10.1111/j.1749-6632.1993.tb38050.x. [DOI] [PubMed] [Google Scholar]
  14. Masu M., Tanabe Y., Tsuchida K., Shigemoto R., Nakanishi S. Sequence and expression of a metabotropic glutamate receptor. Nature. 1991 Feb 28;349(6312):760–765. doi: 10.1038/349760a0. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. 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]
  17. Ohishi H., Shigemoto R., Nakanishi S., Mizuno N. Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat. Neuroscience. 1993 Apr;53(4):1009–1018. doi: 10.1016/0306-4522(93)90485-x. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. 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]
  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]

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