Syntheses and conformational analyses of glutamate analogs: 2-(2-carboxy-3-substituted-cyclopropyl)glycines as useful probes for excitatory amino acid receptors

Journal of Medicinal Chemistry

Volumn 39, Issue 2, 1996, Pages 407-423

  Shimamoto, Keiko ^a   Ohfune, Yasufumi ^a  

^a SUNTORY INSTITUTE FOR BIOORGANIC RESEARCH   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

2 (2 CARBOXYCYCLOPROPYL)GLYCINE DERIVATIVE; 2 [2 CARBOXY 3 (METHOXYMETHYL)CYCLOPROPYL]GLYCINE DERIVATIVE; AMPA RECEPTOR; CYCLOPROPANE DERIVATIVE; EXCITATORY AMINO ACID RECEPTOR; GLUTAMIC ACID DERIVATIVE; KAINIC ACID RECEPTOR; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; RECEPTOR SUBTYPE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; DEPOLARIZATION; DRUG CONFORMATION; DRUG SYNTHESIS; NEUROTRANSMISSION; NEWBORN; NONHUMAN; PH; PROTON NUCLEAR MAGNETIC RESONANCE; RAT; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

ANIMALS; CENTRAL NERVOUS SYSTEM; GLUTAMATES; GLYCINE; MAGNETIC RESONANCE SPECTROSCOPY; MOLECULAR CONFORMATION; MOLECULAR PROBES; RATS; RECEPTORS, GLUTAMATE;

EID: 0030045674     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9502908     Document Type: Article

References (104)

1. (a) 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.
2. (b) Watkins, J. C.; Krogsgaard-Larsen, P.; Honorè, T. Structure, activity relationships in the development of excitatory amino acid receptor agonists and competitive antagonists. Trends Pharmacol. Sci. 1990, 11, 25-53.
3. (a) Collingridge, G. L.; Bliss, T. V. P. NMDA receptor-their role in long-term potentiation. Trends Neurosci. 1987, 10, 288-293.
4. (b) Madison, D. V.; Malenka, R. C.; Nicoll, R. A. Mechanisms underlying long-term potentiation of synaptic transmission. Annu. Rev. Neurosci. 1991, 14, 379-397.
5. (c) Kaba, H.; Hayashi, Y.; Higuchi, T.; Nakanishi, S. Induction of an olfactory memory by the activation of a metabotropic glutamate receptor. Science 1994, 265, 262-264.
6. (a) Meldrum, B.; Garthwaite, J. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol. Sci. 1990, 11, 379-387.
7. (b) Olney, J. W. Excitotoxic amino acids and neuropsychiatrie disorders. Annu. Rev. Pharmacol. Toxicol. 1990, 30, 47-71.
8. (c) Choi, D. W.; Rothman, S. M. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu. Rev. Neurosci. 1990, 13, 171-182.
9. (a) Sladeczek, F.; Pin, J. P.; Recasens, M.; Bockaert, J.; Weiss, S. Glutamate stimulates inositol phosphate formation in striatal neurons. Nature 1985, 317, 717-719.
10. (b) Palmer, E.; Monaghan, D. T.; Cotman, C. W. Trans-ACPD, a selective agonist of phosphoinositide-coupled excitatory amino acid receptors. Eur. J. Pharmacol. 1989, 166, 585-597.
11. mGluRs of rat brain have been cloned and subdivided into mGluR1-7. It has been reported that mGluR1 and -5 were coupled with a stimulation of an intracellular IPs hydrolysis and mGluR2-4, -6, and -7 were negatively coupled to adenyl cyclase activity. (a) Tanabe, Y.; Masu, M.; Ishii, T.; Shigemoto, R.; Nakanishi, S. A family of metabotropic glutamate receptors. Neuron 1992, 8, 169-179. (b) 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, 366, 687-688.
12. mGluRs of rat brain have been cloned and subdivided into mGluR1-7. It has been reported that mGluR1 and -5 were coupled with a stimulation of an intracellular IPs hydrolysis and mGluR2-4, -6, and -7 were negatively coupled to adenyl cyclase activity. (a) Tanabe, Y.; Masu, M.; Ishii, T.; Shigemoto, R.; Nakanishi, S. A family of metabotropic glutamate receptors. Neuron 1992, 8, 169-179. (b) 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, 366, 687-688.
13. Nakanishi, S. Molecular diversity of glutamate receptors and implications for brain function. Science 1992, 258, 597-603 and references cited therein.
14. (a) For the 3-point binding hypothesis, see: Curtis, D. R.; Phillis, J. W.; Watkins, J. C. Actions of amino-acids on the isolated hemisected spinal cord of the toad. Br. J. Pharmacol. 1961, 16, 262-283.
15. (b) For a proposed conformational requirement of NMDA receptors, see: Davies, J.; Evans, R. H.; Francis, A. A.; Jones, D.; Smith, A. S.; Watkins, J. C. Conformational aspects of the actions of some piperidine dicarboxylic acids at excitatory amino acid receptors in the mammalian and amphibian spinal cord. Neurochem. Res. 1982, 7, 1119-1133.
16. (a) Yamanoi, K.; Ohfune, Y.; Watanabe, K.; Li, P.-N.; Takeuchi, H. Synthesis of trans- and cis-α-(carboxycyclopropyl)glycines. Novel neuroinhibitory amino acids as L-glutamate analogue. Tetrahedron Lett. 1988, 29, 1181-1184.
17. (b) Shimamoto, K.; Ishida, M.; Shinozaki, H.; Ohfune, Y. Synthesis of four diastereomeric L-2-(carboxycyclopropyl)glycines. Conformationally constrained L-glutamate analogues. J. Org. Chem. 1991, 56, 4167-4176.
18. (c) CCGs are now commercially available from Tocris Cookson Ltd., Bristol, U.K.
19. (a) Shinozaki, H.; Ishida, M.; Shimamoto, K.; Ohfune, Y. A conformationally restricted analogue of L-glutamate, the (2S,3R,4S) isomer of L-α-(carboxycyclopropyl)glycine, activates the NMDA-type receptor more markedly than NMDA in the isolated rat spinal cord. Brain Res. 1989, 480, 355-359.
20. (b) Shinozaki, H.; Ishida, M.; Shimamoto, K.; Ohfune, Y. Potent NMDA-like actions and potentiation of glutamate receptors by conformational variants of a glutamate analogue in the rat spinal cord. Br. J. Pharmacol. 1989, 98, 1213-1224.
21. 2+ concentration induced by (2S,3R,4S)-2-(carboxycyclopropyl)glycine, a new potent agonist, in cultured rat hippocampal neurones. Brain Res. 1991, 567, 342-345.
22. 2+ increase. Eur. J. Pharmacol. 1992, 211, 195-202.
23. 3H]glutamate transport activity: pharmacologic specificity and regulation by sodium and potassium. J. Neurochem. 1993, 60, 167-179.
24. (f) Nakamura, Y.; Kataoka, K.; Ishida, M.; Shinozaki, H. (2S,3S,4R)-2-(Carboxycyclopropyl)glycine, a potent and competitive inhibitor of both glial and neuronal uptake of glutamate. Neuropharmacology 1993, 32, 833-837.
25. (a) Nakagawa, Y.; Saitoh, K.; Ishihara, T.; Ishida, M.; Shinozaki, H. (2S,3S,4S)-α-(Carboxycyclopropyl)glycine is a novel agonist of metabotropic glutamate receptors. Eur. J. Pharmacol. 1990, 184, 205-206.
26. (b) 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, 537, 311-314.
27. (c) 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, 107, 539-543.
28. (d) 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, 109, 1169-1177.
29. Ohfune, Y.; Shinozaki, H. L-2-(Carboxycyclopropyl)glycines: conformationally constrained L-glutamate analogues. In Drug Design for Neuroscience; Kozikowski, A. P., Ed.; Raven Press: New York, 1993; pp 261-283.
30. Parts of the synthesis and pharmacological profile of MCGs were published in preliminary reports. (a) Shimamoto, K.; Ohfune, Y. Syntheses of 3′-substituted-2-(carboxycyclopropyl)glycines via intramolecular cyclopropanation. The folded form of L-glutamate activates the non-NMDA receptor subtype. Tetrahedron Lett. 1990, 31, 4049-4052. (b) Shimamoto, K.; Ohfune, Y. Inversion of cis-substituted α-cyclopropyl acyl anion. Stereoselective entry to the synthesis of a potent metabotropic glutamate agonist, (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine (L-CCG-I), and its 3′-substituted analogues. Synlett 1993, 919-920.
31. Parts of the synthesis and pharmacological profile of MCGs were published in preliminary reports. (a) Shimamoto, K.; Ohfune, Y. Syntheses of 3′-substituted-2-(carboxycyclopropyl)glycines via intramolecular cyclopropanation. The folded form of L-glutamate activates the non-NMDA receptor subtype. Tetrahedron Lett. 1990, 31, 4049-4052. (b) Shimamoto, K.; Ohfune, Y. Inversion of cis-substituted α-cyclopropyl acyl anion. Stereoselective entry to the synthesis of a potent metabotropic glutamate agonist, (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine (L-CCG-I), and its 3′-substituted analogues. Synlett 1993, 919-920.
32. (a) Garner, P.; Park, J. M. 1,1-Dimethylethyl (S)- or (R)-4-formyl-2,2-dimethyl-3-oxazolidine carboxylate: a useful serinal derivative. Org. Synth. 1991, 70, 18-28.
33. (b) Garner, P.; Park, J. M. The synthesis and configurational stability of differentially protected β-hydroxy-α-amino aldehyde. J. Org. Chem. 1987, 52, 2361-2364.
34. Sakai, N.; Ohfune, Y. Total synthesis of galantin I. Acid-catalyzed cyclization of galantinic acid. J. Am. Chem. Soc. 1992, 114, 998-1010.
35. (a) Sakaitani, M.; Ohfune, Y. Selective transformation of N-t-butoxycarbonyl group into N-alkoxycarbonyl group via N-carboxylate ion equivalent. Tetrahedron Lett. 1985, 26, 5543-5546.
36. (b) Sakaitani, M.; Ohfune, Y. Syntheses and reactions of silyl carbamates. 1. Chemoselective transformation of amino protective groups via tert-butyldimethylsilyl carbamates. J. Org. Chem. 1990, 55, 870-876.
37. The exclusive exo cycloaddition might be attributed to its putative transition state conformation 4 which is sterically more favorable than that of the endo transition state.
38. 2 was purified prior to use (see the Experimental Section). We thank Professor M. Mandai, Okayama University of Science, for informing us of this purification procedure.
39. Methylation of the primary alcohol using NaH/MeI was not satisfactory since a considerable amount of N-methylated byproduct was also obtained.
40. Ohfune, Y.; Shimamoto, K.; Ishida, M.; Shinozaki, H. Synthesis of L-2-(2,3-dicarboxycyclopropyl)glycines. Novel conformationally restricted glutamate analogues. Bioorg. Med. Chem. Lett. 1993, 3, 15-18.
41. Prepared from (2S,1′S,2′R)-n-(tert-butoxycarbonyl)-2-[(ethoxycarbonyl)cyclopropyl] glycinol. (a) Shimamoto, K.; Ohfune, Y. New routes to the synthesis of cis-α-(carboxycyclopropyl)glycines from L-glutamic acid. Conformationally constrained analogues of the excitatory neurotransmitter L-glutamic acid. Tetrahedron Lett. 1980, 30, 3803-3894. (b) See ref 8b.
42. Prepared from (2S,1′S,2′R)-n-(tert-butoxycarbonyl)-2-[(ethoxycarbonyl)cyclopropyl] glycinol. (a) Shimamoto, K.; Ohfune, Y. New routes to the synthesis of cis-α-(carboxycyclopropyl)glycines from L-glutamic acid. Conformationally constrained analogues of the excitatory neurotransmitter L-glutamic acid. Tetrahedron Lett. 1980, 30, 3803-3894. (b) See ref 8b.
43. 2.
44. Bordwell, F. G. Equilibrium acidities in dimethyl sulfoxide solution. Acc. Chem. Res. 1988, 21, 456-463.
45. Pyramidal α-cyclopropyl ester anion has been reported. (a) Reissig, H.-U.; Böhm, I. High diastereoselection in the alkylation of siloxy-substituted methyl cyclopropanecarboxylates: consequence of a pyramidal ester enolate anion? J. Am. Chem. Soc. 1982, 104, 1735-1737. (b) Reissig, H.-U. Donor-acceptor-substituted cyclopropanes: versatile building blocks in organic synthesis. Topics in Current Chemistry; Springer-Verlag: Berlin, 1988; Vol. 144, pp 75-135.
46. Pyramidal α-cyclopropyl ester anion has been reported. (a) Reissig, H.-U.; Böhm, I. High diastereoselection in the alkylation of siloxy-substituted methyl cyclopropanecarboxylates: consequence of a pyramidal ester enolate anion? J. Am. Chem. Soc. 1982, 104, 1735-1737. (b) Reissig, H.-U. Donor-acceptor-substituted cyclopropanes: versatile building blocks in organic synthesis. Topics in Current Chemistry; Springer-Verlag: Berlin, 1988; Vol. 144, pp 75-135.
47. (a) Walborsky, H. M.; Hornyak, F. M. Cyclopropanes: the cyclopropyl carbanion. J. Am. Chem. Soc. 1955, 77, 6026-6029.
48. (b) Walborsky, H. M.; Motes, J. M. Cyclopropanes. XXV. The cyclopropyl anion. J. Am. Chem. Soc. 1970, 92, 2445-2450.
49. (c) van Wijnen, Th.; Steinberg, H.; de Boer, Th. J. The chemistry of small ring compounds-XIV. Acidity of cyclopropanes with electron-withdrawing substituents. Tetrahedron 1972, 28, 5423-5432.
50. Martin, S. F.; Austin, R. E.; Oalmann, C. J. Stereoselective synthesis of 1,2,3-trisubstituted cyclopropanes as novel dipeptide isosteres. Tetrahedron Lett 1990, 31, 4731-4734.
51. Ishida, M.; Ohfune, Y.; Shimada, Y.; Shimamoto, K.; Shinozaki, H. Changes in preference for receptor subtypes of configurational variants of a glutamate analog: conversion from the NMDA-type to the non-NMDA type. Brain Res. 1991, 550, 152-156.
52. Ishida, M.; Saitoh, T.; Tsuji, K.; Nakamura, Y.; Kataoka, K.; Shinozaki, H. Novel agonists for metabotropic receptors: trans-and cis-2-(2-carboxy-3-methoxymethylcyclopropyl)glycine (trans-and cis-MCG-I). Neuropharmacology 1995, 34, 821-827.
53. Ishida, M.; Saitoh, T.; Nakamura, Y.; Kataoka, K.; Shinozaki, H. A novel metabotropic receptor agonist: (2S,1′S,2′R,3′R)-2-(2-carboxy-3-methoxymethylcyclopropyl) glycine (cis-MCG-I). Eur. J. Pharmacol., Mol. Pharmacol. Sect. 1994, 268, 267-270.
54. For presynaptic inhibition, see: (a) Sunter, D. C.; Edgar, G. E.; Pook, P. C.; Howard, J. A. K.; Udvarhelyi, P. M.; Watkins, J. C. Actions of the four isomers of 1-aminocyclopentane-1,3-dicarboxylate (ACPD) in the hemisected isolated spinal cord of the neonatal rat. Br. J. Pharmacol. 1991, 104, 377P. (b) Cotman, C. W.; Flatman, J. A.; Ganong, A. H.; Perkius, M. N. Effects of excitatory amino acid antagonists on evoked and spontaneous excitatory potentials in guinea-pig hippocampus. J. Physiol. 1986, 378, 403-415.
55. For presynaptic inhibition, see: (a) Sunter, D. C.; Edgar, G. E.; Pook, P. C.; Howard, J. A. K.; Udvarhelyi, P. M.; Watkins, J. C. Actions of the four isomers of 1-aminocyclopentane-1,3-dicarboxylate (ACPD) in the hemisected isolated spinal cord of the neonatal rat. Br. J. Pharmacol. 1991, 104, 377P. (b) Cotman, C. W.; Flatman, J. A.; Ganong, A. H.; Perkius, M. N. Effects of excitatory amino acid antagonists on evoked and spontaneous excitatory potentials in guinea-pig hippocampus. J. Physiol. 1986, 378, 403-415.
56. 3 = 9.67. Merck Index, 8th ed.; Merck & Co., Inc.: Rathway, NJ, 1989; p 4363.
57. a values of kainic acid, see: Ueno, Y.; Nawa, H.; Ueyanagi, J.; Morimoto, H.; Nakamori, R.; Matsuoka, T. Studies on the active components of Digenea simplex Ag, and related compounds, I. Studies on the structure of kainic acid (1). Yakugaku Zasshi 1955, 75, 807-811.
58. Barret, G. C.; Davies, J. S. Nuclear magnetic resonance spectra of amino acids and their derivatives. In Chemistry and biochemistry of the amino acids; Barret, G. C., Ed.; Chapman and Hall: New York, 1985; pp 525-544.
59. 1H NMR.
60. The C-2H of CCG-IV was observed as a broad signal at pH 9-11 where slow exchange of the nonprotonated and the protonated amino group might affect the broadening of the signal at C-2H.
61. 2H-1′H values of trans-MCG-III and -IV (pH > 8-0) and cis-MCG-IV (pH > 9) could not be obtained because of the broadening signals of both 2H and 1′H.
62. For an example of molecular mechanics calculation of glutamate analogs, see: Bridges, R. J.; Lovering, F. E.; Humphrey, J. M.; Stanley, M. S.; Blakely, T. N.; Cristofaro, M. F.; Chamberlin, A. R. Conformationally restricted inhibitors of the high affinity L-glutamate transporter. Bioorg. Med. Chem. Lett. 1993, 3, 115-121.
63. The rotation of both the carboxylates of CCGs did not affect the minimization.
64. Calculations of cis-MCG-I and -IV were performed by rotating the C2-C1′ bond and the two bonds of the C3′ methoxymethyl group (in 60° increments) and provided 32 and 23 minimized structures, respectively. Among them, the existence ratio of the H-C2-C1′-H antiperiplanar type conformers were 96.6% for cis-MCG-I and 99.3% for cis-MCG-IV. These results were in good agreement with those of Me-substituted CCGs.
65. We thank Dr. N. Hamanaka, Director, Minase Research Institute of Ono Pharmaceutical Co. Ltd., for X-ray crystallographic analysis of CCGs. We could not prepare crystals of CCG-I suitable for X-ray crystallographic analysis because this compound formed fine powders under numerous recrystallization conditions.
66. - (Tor 1 = -173.0°, Tor 2 = -73.1°), respectively, (a) Lehmann, M. S.; Nunes, A. C. A short hydrogen bond between near identical carboxyl group in the α modification of L-glutamic acid. Acta Crystallogr. 1980, B36, 1621-1625. (b) Lehmann, M. S.; Koetzle, T. F.; Hamilton, W. C. Precision neutron diffraction structure determination of protein and nucleic acid components. VIII: the crystal and molecular structure of the β-form of the amino acid L-glutamic acid. J. Crystallogr. Mol. Struct. 1972, 2, 225-233.
67. - (Tor 1 = -173.0°, Tor 2 = -73.1°), respectively, (a) Lehmann, M. S.; Nunes, A. C. A short hydrogen bond between near identical carboxyl group in the α modification of L-glutamic acid. Acta Crystallogr. 1980, B36, 1621-1625. (b) Lehmann, M. S.; Koetzle, T. F.; Hamilton, W. C. Precision neutron diffraction structure determination of protein and nucleic acid components. VIII: the crystal and molecular structure of the β-form of the amino acid L-glutamic acid. J. Crystallogr. Mol. Struct. 1972, 2, 225-233.
68. For previous conformational studies of glutamate, see: Ham, N. S. NMR studies of solution conformation of physiologically active amino-acids. In Molecular and Quantum Pharmacology; Bergmann, E., Pullman, B., Eds.; D. Reidel Publishing: Dordrecht, 1974; pp 261-268.
69. For a review describing proposed conformational requirements of glutamate receptors based on the known glutamate agonists, see: Chamberlin, R.; Bridges, R. Conformationally constrained acidic amino acids as probes of glutamate receptors and transporters. In Drug Design for Neuroscience; Kozikowski, A. P., Ed.; Raven Press; New York, 1993; pp 231-259.
70. 2c,5b,10d,19 although at high concentrations this compound binds to NMDA receptors. We believe that the extended partial structure of DCG-IV also contributes to its potent activity to mGluRs.
71. 2+ mobilization in rat cerebellar neurons. Eur. J. Pharmacol. 1990, 186, 363-365.
72. The rms value of E and CCG-I (antiperiplanar conformer) was 0.117 Å.
73. CMP-II and -III have already been synthesized and characterized as L-syn-exo-MPDC and L-anti-endo-MPDC, respectively. Bridges, R. J.; Levering, F. E.; Koch, H.; Cotman, C. W.; Chamberlin, A. R. A conformationally constrained competitive inhibitor of the sodium-dependent glutamate transporter in forebrain synaptosomes: L-anti-endo-3,4-methanopyrrolidine dicarboxylate. Neuroscience Lett. 1994, 174, 193-197.
74. 2O).
75. Unpublished observations using electrophysiological method in the new born rat isolated spinal cord. There would be many reasons why CMPs are inactive to the receptors (e.g., steric hindrance, transport difficulties, and no flexibility to change its conformation). These factors could not be ruled out by the present studies.
76. (a) Watkins, J. C. NMDA receptors: agonists and competitive antagonists. In Trends in Medicinal Chemistry, 90; Sarel, S., Mechoulam, R., Agranat, I., Eds.; IUPAC/Blackwell Scientific Publications: New York, 1992; pp 17-29.
77. (b) Jane, D. E.; Olverman, H. J.; Watkins, J. C. Agonists and competitive antagonists: Structure-activity and molecular modelling studies. In The NMDA receptor, 2nd ed.; Watkins, J. C., Collingridge, G. L., Eds.; Oxford University Press: London, 1994; pp 31-104.
78. (a) O'Callaghan, D.; Wong, M. G.; Beart, P. M. Molecular modelling of N-methyl-L-aspartate receptor agonists. Mol. Neuropharmacol. 1992, 2, 89-92.
79. (b) Kyle, D. J.; Patch, R. J.; Karbon, E. W.; Ferkany, J. W. NMDA receptors: heterogeneity and agonism. In Excitatory amino acid receptors. Design of agonists and antagonists; Krogsgaard-Larsen, P., Hansen, J. J., Eds.; Ellis Horwood Ltd.: Chichester, U.K., 1992; pp 121-162.
80. Ortwine, D. F.; Malone, T. C.; Bigge, C. F.; Drummond, J. T.; Humblet, C.; Johnson, G.; Pinter, G. W. Generation of N-methyl-D-aspartate agonists and competitive antagonist pharmacophore models. Design and synthesis of phosphonoalkyl-substituted tetrahydroisoquinolines as novel antagonists. J. Med. Chem. 1992, 35, 1345-1370.
81. (a) Lanthorn, T. H.; Hood, W. F.; Watson, G. B.; Compton, R. P.; Rader, R. K.; Gaoni, Y.; Monahan, J. B. cis-2,4-Methanoglutamate is a potent and selective N-methyl-D-aspartate receptor agonist. Eur. J. Pharmacol. 1990, 182, 397-404.
82. (b) Allan, R. D.; Hanrahan, J. R.; Hambley, T. W.; Johnston, G. A. R.; 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, 33, 2905-2915.
83. The rms values of I and L with CCG-IV (antiperiplanar conformer) were 0.078 and 0.280 Å, respectively.
84. 2O).
85. (a) Hashimoto, K.; Shirahama, H. Syntheses of kainoids. J. Synth. Org. Chem. Jpn. 1989, 47, 212-223.
86. (b) Hashimoto, K.; Shirahama, H. Synthesis and neuroexcitatory activity of new kainoids. In Amino acids: Chemistry, Biology and Medicine; Lubec, G., Rosenthal, G. A., Eds.; ESCOM: Leiden, 1990; pp 566-572.
87. (c) Ishida, M.; Shinozaki, H. Novel kainate derivatives: potent depolarizing actions on spinal motoneurones and dorsal root fibers in newborn rats. Br. J. Pharmacol. 1991, 104, 873-878.
88. (a) Blake, J. F.; Jane, D. E.; Watkins, J. C. Action of willardiin analogues on immature rat dosal root. Br. J. Pharmacol. 1991, 104, 334P. Wong, L. A.; Mayer, M. L.; Jane, D. E.; Watkins, J. C. Willardiines differentiate agonist binding site for kainate-versus AMPA-preferring glutamate receptors in DRG and hippocampal neurones. J. Neurosci. 1994, 14, 3881-3897.
89. (a) Blake, J. F.; Jane, D. E.; Watkins, J. C. Action of willardiin analogues on immature rat dosal root. Br. J. Pharmacol. 1991, 104, 334P. Wong, L. A.; Mayer, M. L.; Jane, D. E.; Watkins, J. C. Willardiines differentiate agonist binding site for kainate-versus AMPA-preferring glutamate receptors in DRG and hippocampal neurones. J. Neurosci. 1994, 14, 3881-3897.
90. (a) Agrawal, S. G.; Evans, R. H. The primary afferent depolarizing action of kainate in the rat. Br. J. Pharmacol. 1986, 87, 345-355.
91. (b) Evans, R. H.; Evans, S. J.; Pook, P. C.; Sunter, D. C. A comparison of excitatory amino acid antagonists acting at primary afferent C fibres and motoneurons of the isolated spinal cord of the rat. Br. J. Pharmacol. 1987, 91, 531-537.
92. Raghavan, S.; Ishida, M.; Shinozaki, H.; Nakanishi, K.; Ohfune, Y. Synthesis of L-2-(2-carboxy-4-methylenecyclopentyl)glycines (CPGs). Novel conformationally restricted glutamate analogues. Tetrahedron Lett. 1993, 34, 5765-5768.
93. 54b
94. 3H]kainic acid. Brain Res. 1983, 265, 169-172. (b) Conway, G. A.; Park, J. S.; Maggiora, L.; Mertes, M. P.; Gallon, N. Palladium(II) catalyzed olefin-coupling reactions of kainic acid: effects of substitution on the isopropenyl group on receptor binding. J. Med. Chem. 1984, 27, 52-56.
95. 3H]kainic acid. Brain Res. 1983, 265, 169-172. (b) Conway, G. A.; Park, J. S.; Maggiora, L.; Mertes, M. P.; Gallon, N. Palladium(II) catalyzed olefin-coupling reactions of kainic acid: effects of substitution on the isopropenyl group on receptor binding. J. Med. Chem. 1984, 27, 52-56.
96. 57 In addition, the C3′R substituent of trans-MCG-IV is essential to activate kainate receptors where CCG-IV and cis-MCG-IV were inactive.
97. (a) Madsen, U.; Wong, E. H. F. Heterocyclic excitatory amino acids. Synthesis and Biological activity of novel analogues of AMPA. J. Med. Chem. 1992, 107-111.
98. (b) Skjaerbaek, N.; Ebert, B.; Falch, E.; Brehm, L.; Krogsgaard-Larsen, P. Excitatory amino acids. Synthesis of (RS)-2-amino-3-(5-cyclopropyl-3-hydroxyisoxazol-4-yl)propionic acid, a new potent and specific AMPA receptor agonist. J. Chem. Soc., Perkin Trans I 1995, 221-225.
99. (c) Lund, T. M.; Madsen, U.; Ebert, B.; Jorgensen, F. S.; Krogsgaard-Larsen, P. Conformational and pharmacological characterization of 4-AHCP, a bicyclic homologue of the excitatory amino acid receptor agonist AMPA. Med. Chem. Res. 1991, 1, 136-141.
100. (a) Sheardown, M. J.; Nielsen, E. Ø.; Hansen, A. J.; Jacobsen, P.; Honoré, T. 2,3-Dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoline: A neuroprotectant for cereberal ischemia. Science 1990, 247, 571-574.
101. (b) Pook, P.; Brugger, F.; Hawkins, N. S.; Clark, K. C.; Watkins, J. C.; Evans, R. H. A comparison of the actions of agonists and antagonists at non-NMDA receptors of C-fibers and motoneurones of the immature rat spinal cord in vivo. Br. J. Phramacol. 1993, 108, 179-184.
102. Ouerfelli, O.; Ishida, M.; Shinozaki, H.; Nakanishi, K.; Ohfune, Y. Efficient synthesis of 4-methylene-L-glutamic acid and its analogues. Synlett 1993, 409-410.
103. (a) Watkins, J. C.; Collingridge, G. C. Phenylglycine derivatives as antagonists of metabotropic glutamate receptors. Trends Pharmacol. Sci. 1994, 15, 333-342.
104. (b) Knöphel, T.; Kuhn, R.; Allgeier, H. Metabotropic glutamate receptors: Novel targets for drug development. J. Med. Chem. 1995, 38, 1417-1426.