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. 1996 Apr;117(7):1493–1503. doi: 10.1111/j.1476-5381.1996.tb15312.x

Structure-activity relationships of new agonists and antagonists of different metabotropic glutamate receptor subtypes.

N Sekiyama 1, Y Hayashi 1, S Nakanishi 1, D E Jane 1, H W Tse 1, E F Birse 1, J C Watkins 1
PMCID: PMC1909443  PMID: 8730745

Abstract

1. We investigated the agonist and antagonist activities of 22 new phenylglycine and phenylalanine derivatives for metabotropic glutamate receptors (mGluRs) by examining their effects on the signal transduction of mGluR1, mGluR2 and mGluR6 subtypes expressed in Chinese hamster ovary cells. This analysis revealed several structural characteristics that govern receptor subtype specificity of the agonist and antagonist activities of phenylglycine derivatives. 2. Hydroxyphenylglycine derivatives possessed either an agonist activity on mGluR1/mGluR6 or an antagonist activity on mGluR1. 3. Carboxyphenylglycine derivatives showed an agonist activity on mGluR2 but an antagonist activity on mGluR1. 4. alpha-Methylation or alpha-ethylation of the carboxyphenylglycine derivatives converts the agonist property for mGluR2 to an antagonist property, thus producing antagonists at both mGluR1 and mGluR2. 5. Structurally-corresponding phenylalanine derivatives showed little or no agonist or antagonist activity on any subtypes of the receptors. 6. This investigation demonstrates that the nature and positions of side chains and ring substituents incorporated into the phenylglycine structure are critical in determining the agonist and antagonist activities of members of this group of compounds on different subtypes of the mGluR family. 7. We also tested two alpha-methyl derivatives of mGluR agonists. (2S, 1'S, 2'S)-2-(2-Carboxycyclopropyl)glycine (L-CCG-I) is a potent agonist for mGluR2 but alpha-methylation of this compound changes its activity to that of an mGluR2-selective antagonist. In contrast, alpha-methylation of L-2-amino-4-phosphonobutyrate (L-AP4) results in retention of an agonist activity on mGluR6. Thus, alpha-methylation produces different effects, depending on the chemical structures of lead compounds and/or on the subtype of mGluR tested.

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Selected References

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  1. Aramori I., Nakanishi S. Coupling of two endothelin receptor subtypes to differing signal transduction in transfected Chinese hamster ovary cells. J Biol Chem. 1992 Jun 25;267(18):12468–12474. [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. 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]
  4. Bliss T. V., Collingridge G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993 Jan 7;361(6407):31–39. doi: 10.1038/361031a0. [DOI] [PubMed] [Google Scholar]
  5. Bushell T. J., Jane D. E., Tse H. W., Watkins J. C., Davies C. H., Garthwaite J., Collingridge G. L. Antagonism of the synaptic depressant actions of L-AP4 in the lateral perforant path by MAP4. Neuropharmacology. 1995 Feb;34(2):239–241. doi: 10.1016/0028-3908(95)00012-u. [DOI] [PubMed] [Google Scholar]
  6. Choi D. W., Rothman S. M. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci. 1990;13:171–182. doi: 10.1146/annurev.ne.13.030190.001131. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Eaton S. A., Birse E. F., Wharton B., Sunter D. C., Udvarhelyi P. M., Watkins J. C., Salt T. E. Mediation of thalamic sensory responses in vivo by ACPD-activated excitatory amino acid receptors. Eur J Neurosci. 1993 Feb 1;5(2):186–189. doi: 10.1111/j.1460-9568.1993.tb00484.x. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Hayashi Y., Momiyama A., Takahashi T., Ohishi H., Ogawa-Meguro R., Shigemoto R., Mizuno N., Nakanishi S. Role of a metabotropic glutamate receptor in synaptic modulation in the accessory olfactory bulb. Nature. 1993 Dec 16;366(6456):687–690. doi: 10.1038/366687a0. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Hayashi Y., Tanabe Y., Aramori I., Masu M., Shimamoto K., Ohfune Y., Nakanishi S. Agonist analysis of 2-(carboxycyclopropyl)glycine isomers for cloned metabotropic glutamate receptor subtypes expressed in Chinese hamster ovary cells. Br J Pharmacol. 1992 Oct;107(2):539–543. doi: 10.1111/j.1476-5381.1992.tb12780.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hollmann M., Heinemann S. Cloned glutamate receptors. Annu Rev Neurosci. 1994;17:31–108. doi: 10.1146/annurev.ne.17.030194.000335. [DOI] [PubMed] [Google Scholar]
  14. Ishida M., Akagi H., Shimamoto K., Ohfune Y., Shinozaki H. A potent metabotropic glutamate receptor agonist: electrophysiological actions of a conformationally restricted glutamate analogue in the rat spinal cord and Xenopus oocytes. Brain Res. 1990 Dec 24;537(1-2):311–314. doi: 10.1016/0006-8993(90)90375-l. [DOI] [PubMed] [Google Scholar]
  15. Ishida M., Saitoh T., Shimamoto K., Ohfune Y., Shinozaki H. A novel metabotropic glutamate receptor agonist: marked depression of monosynaptic excitation in the newborn rat isolated spinal cord. Br J Pharmacol. 1993 Aug;109(4):1169–1177. doi: 10.1111/j.1476-5381.1993.tb13745.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ito I., Kohda A., Tanabe S., Hirose E., Hayashi M., Mitsunaga S., Sugiyama H. 3,5-Dihydroxyphenyl-glycine: a potent agonist of metabotropic glutamate receptors. Neuroreport. 1992 Nov;3(11):1013–1016. [PubMed] [Google Scholar]
  17. 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]
  18. Jane D. E., Jones P. L., Pook P. C., Tse H. W., Watkins J. C. Actions of two new antagonists showing selectivity for different sub-types of metabotropic glutamate receptor in the neonatal rat spinal cord. Br J Pharmacol. 1994 Jul;112(3):809–816. doi: 10.1111/j.1476-5381.1994.tb13151.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Knöpfel T., Kuhn R., Allgeier H. Metabotropic glutamate receptors: novel targets for drug development. J Med Chem. 1995 Apr 28;38(9):1417–1426. doi: 10.1021/jm00009a001. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Nakanishi S., Masu M. Molecular diversity and functions of glutamate receptors. Annu Rev Biophys Biomol Struct. 1994;23:319–348. doi: 10.1146/annurev.bb.23.060194.001535. [DOI] [PubMed] [Google Scholar]
  23. Nakanishi S. Metabotropic glutamate receptors: synaptic transmission, modulation, and plasticity. Neuron. 1994 Nov;13(5):1031–1037. doi: 10.1016/0896-6273(94)90043-4. [DOI] [PubMed] [Google Scholar]
  24. Nakanishi S. Molecular diversity of glutamate receptors and implications for brain function. Science. 1992 Oct 23;258(5082):597–603. doi: 10.1126/science.1329206. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Salt T. E., Eaton S. A. Distinct presynaptic metabotropic receptors for L-AP4 and CCG1 on GABAergic terminals: pharmacological evidence using novel alpha-methyl derivative mGluR antagonists, MAP4 and MCCG, in the rat thalamus in vivo. Neuroscience. 1995 Mar;65(1):5–13. doi: 10.1016/0306-4522(94)00464-g. [DOI] [PubMed] [Google Scholar]
  27. Schoepp D. D., Conn P. J. Metabotropic glutamate receptors in brain function and pathology. Trends Pharmacol Sci. 1993 Jan;14(1):13–20. doi: 10.1016/0165-6147(93)90107-u. [DOI] [PubMed] [Google Scholar]
  28. Schoepp D. D., Goldsworthy J., Johnson B. G., Salhoff C. R., Baker S. R. 3,5-dihydroxyphenylglycine is a highly selective agonist for phosphoinositide-linked metabotropic glutamate receptors in the rat hippocampus. J Neurochem. 1994 Aug;63(2):769–772. doi: 10.1046/j.1471-4159.1994.63020769.x. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Watkins J. C., Krogsgaard-Larsen P., Honoré T. Structure-activity relationships in the development of excitatory amino acid receptor agonists and competitive antagonists. Trends Pharmacol Sci. 1990 Jan;11(1):25–33. doi: 10.1016/0165-6147(90)90038-a. [DOI] [PubMed] [Google Scholar]
  31. 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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