Ionotropic Glutamate Receptors
Basic Neuropharmacology
David Bleakman,
Andrew Alt,
David Lodge, Daniel T. Monaghan,
David E. Jane, Eric S. Nisenbaum,
David Bleakman
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
Search for more papers by this authorAndrew Alt
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
Search for more papers by this authorDaniel T. Monaghan
University of Nebraska Medical Center, Omaha, Nebraska
Search for more papers by this authorEric S. Nisenbaum
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
Search for more papers by this authorDavid Bleakman,
Andrew Alt,
David Lodge, Daniel T. Monaghan,
David E. Jane, Eric S. Nisenbaum,
David Bleakman
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
Search for more papers by this authorAndrew Alt
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
Search for more papers by this authorDaniel T. Monaghan
University of Nebraska Medical Center, Omaha, Nebraska
Search for more papers by this authorEric S. Nisenbaum
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
Search for more papers by this authorAbstract
Since their discovery in the 1950s, ionotropic glutamate receptors represent a class of receptor proteins that mediate fast excitatory transmission in the central nervous system. In this chapter, we describe the extensive studies of agents that act at the various subtypes of ionotropic glutamate receptor and how these agents have been used to delineate the physiological and pathophysiological roles of these receptors.
References
- 1 Davies, J., Evans, R. H., Francis, A. A., and Watkins, J. C. (1979). Excitatory amino acid receptors and synaptic excitation in the mammalian central nervous system. J. Physiol. (Paris) 75, 641–654.
- 2 McLennan, H., and Lodge, D. (1979). The antagonism of amino acid-induced excitation of spinal neurones in the cat. Brain Res. 169, 83–90.
- 3 Watkins, J. C., and Evans, R. H. (1981). Excitatory amino acid transmitters. Annu. Rev. Pharmacol. Toxicol. 21, 165–204.
- 4 Sladeczek, F., Pin, J. P., Recasens, M., Bockaert, J., and Weiss, S. (1985). Glutamate stimulates inositol phosphate formation in striatal neurons. Nature 317, 717–719.
- 5 Nicoletti, F., Meek, J. L., Iadarola, M. J., Chuange, D. M., Roth, B. L., and Costa, E. (1986). Coupling of inositol phospholipid metabolism with excitatory amino acid recognition sites in rat hippocampus. J. Neurochem. 46, 40–46.
- 6 Krogsgaard-Larsen, P., Honoré, T., Hansen, J. J., Curtis, D. R., and Lodge, D. (1980). New class of glutamate agonist structurally related to ibotenic acid. Nature 284, 64–66.
- 7 Collingridge, G. L., and Lester, R. A. J. (1989). Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacol. Rev. 40, 143–210.
- 8 Dingledine, R., Borges, K., Bowie, D., and Traynelis, S. F. (1999). The glutamate receptor ion channels. Pharmacol. Rev. 51, 7–61.
- 9 Danbolt, M. C. (2001). Glutamate update. Prog. Neurobiol. 65, 1–105.
- 10 Bridges, R. J., and Esslinger, C. S. (2005). The excitatory amino acid transporters: Pharmacological insights on substrate and inhibitor specificity of the EAAT subtypes. Pharmacol. Therapeut. 107, 271–285.
- 11 Fremeau, R. T., Voglmaser, S., Seal, R. P., and Edwards, R. H. (2004). VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate. Trends Neurosci. 27, 89–103.
- 12 McKenna, M. C., Stevenson, J. H., Huang, X., and Hopkins, I. B. (2000). Differential distribution of the enzymes glutamate dehydrogenase and aspartate aminotransferase in cortical synaptic mitochondria contributes to metabolic compartmentation in cortical synaptic terminals. Neurochem. Int. 37, 229–241.
- 13 Armstrong, N., Sun, Y., Chen, G.-Q., and Gouaux, E. (1998). Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature 395, 913–917.
- 14 Gouaux, E. (2003). Structure and function of AMPA receptors. J. Physiol. 554, 243–249.
- 15 Curtis, D. R., and Watkins, J. C. (1960). The excitation and depression of spinal neurones by structurally related amino acids. J. Neurochem. 6, 117–141.
- 16 Watkins, J. C. (1962). The synthesis of some acidic amino acids possessing neuropharmacological activity. J. Med. Pharmacol. Chem. 5, 1187–1199.
- 17 Curtis, D. R., and Watkins, J. C. (1963). Acidic amino acids with strong excitatory actions on mammalian neurones. J. Physiol. 166, 1–14.
- 18 Evans, R. H., Francis, A. A., and Watkins, J. C. (1977). Selective antagonism by Mg2+ of amino acid-induced depolarization of spinal neurones. Experientia 33, 489–491.
- 19 Biscoe, T. J., Davies, J., Dray, A., Evans, R. H., Francis, A. A., Martin, M. R., and Watkins, J. C. (1977). Depression of synaptic excitation and of amino acid-induced excitatory responses of spinal neurones by d-α-aminoadipate, α,ɛ-diaminopimelic acid and HA-966. Eur. J. Pharmacol. 45, 315–316.
- 20 Biscoe, T. J., Evans, R. H., Francis, A. A., Martin, M. R., Watkins, J. C., Davies, J., and Dray, A. (1977). d-α-Aminoadipate as a selective antagonist of amino acid-induced and synaptic excitation of mammalian spinal neurones. Nature 270, 743–745.
- 21 Hall, J. G., Mclennan, H., and Wheal, H. V. (1977). The actions of certain amino acids on neuronal excitants. J. Physiol. 272, 52–53.
- 22 Evans, R. H., Francis, A. A., and Watkins, J. C. (1978). Mg2+-like selective antagonism of excitatory amino acid-induced responses by α,ɛ-diaminopimelic acid, d-α-aminoadipate and HA-966 in isolated spinal cord of frog and immature rat. Brain Res. 148, 536–542.
- 23 Lodge, D., Headley, P. M., and Curtis, D. R. (1978). Selective antagonism by d-alpha-aminoadipate of amino acid and synaptic excitation of cat spinal neurones. Brain Res. 152, 603–608.
- 24 Evans, R. H., Francis, A. A., Jones, A. W., Smith, D. A. S., and Watkins, J. C. (1982). The effects of a series of ω-phosphonic α-carboxylic amino acids on electrically evoked and amino acid induced responses in isolated spinal cord preparations. Br. J. Pharmacol. 75, 65–75.
- 25 Collingridge, G. L., Kehl, S. J., and McLennan, H. (1983). Excitatory amino acids in synaptic transmission in the Schaffer collateral-commisural pathway of the rat hippocampus. J. Physiol. 334, 33–46.
- 26 Meldrum, B. S. (1985). Possible therapeutic applications of antagonists of excitatory amino acid neurotransmitters. Clini. Sci. 68, 113–122.
- 27 Croucher, M. J., Collins, J. F., and Meldrum, B. S. (1982). Anticonvulsant action of excitatory amino acid antagonists. Science 216, 899–901.
- 28 D. Lodge, W. Danysz, and C. G. Parsons, Eds. (2002). Ionotropic Glutamate Receptors as Therapeutic Targets. F. P. Graham Publishing, Johnson City, TN.
- 29 O'Neill, M. J., and Lees, K. R. (2002). Stroke. In Ionotropic Glutamate Receptors as Therapeutic Targets, D. Lodge, W. Danysz, and C. G. Parsons, Eds. F. P. Graham Publishing, Johnson City, TN, pp. 403–446.
- 30 Loscher, W., and Rogawski, M. A. (2002). Epilepsy. In Ionotropic Glutamate Receptors as Therapeutic Targets, D. Lodge, W. Danysz, and C. G. Parsons, Eds. F. P. Graham Publishing, Johnson City, TN, pp. 91–132.
- 31 Chizh, B. A., and Eide, P. K. (2002). Pain. In Ionotropic Glutamate Receptors as Therapeutic Targets, D. Lodge, W. Danysz, and C. G. Parsons, Eds. F. P. Graham Publishing, Johnson City, TN, pp. 263–300.
- 32 Anis, N. A., Berry, S. C., Burton, N. R., and Lodge, D. (1983). The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurons by N-methyl-d-aspartate. Br. J. Pharmacol. 79, 565–575.
- 33 Lodge, D., and Johnson, K. M. (1990). Noncompetitive excitatory amino acid antagonists. Trends Pharmacol. Sci. 11, 81–86.
- 34 Lodge, D., and Berry, S. C. (1984). Psychotomimetic effects of sigma opiates may be mediated by block of central excitatory synapses utilizing receptors for aspartate-like amino acids. In Modulation of Sensory Motor Activity During Altered Behavioural States, R. Bandler, Ed. Alan R. Liss, New York, pp. 503–518.
- 35 Javitt, D. C. (2002). Schizophrenia. In Ionotropic Glutamate Receptors as Therapeutic Targets, D. Lodge, W. Danysz, and C. G. Parsons, Eds. F. P. Graham Publishing, TN, pp. 151–183.
- 36 Johnson, J. W., and Ascher, P. (1987). Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325, 529–531.
- 37 Kleckner, N. W., and Dingledine, R. (1988). Requirement for glycine in activation of NMDA receptors expressed in Xenopus oocytes. Science 241, 835–837.
- 38 Ransom, R. W., and Stec, N. L. (1988). Cooperative modulation of [3H]MK-801 binding to the N-methyl-d-aspartate receptor-ion channel complex by l-glutamate, glycine, and polyamines. J. Neurochem. 51, 830–836.
- 39 Monyer, H., Sprengel, R., Schoepfer, R., Herb, A., Higuchi, M., Lomeli, H., Burnashev, N., Sakmann, B., and Seeburg, P. H. (1992). Heteromeric NMDA receptors: Molecular and functional distinction of subtypes. Science 256, 1217–1221.
- 40 Furukawa, H., Singh, S. K., Mancusso, R., and Gouaux, E. (2005). Subunit arrangement and function in NMDA receptors. Nature 438, 185–192.
- 41 Chatterton, J. E., Awobuluyi, M., Premkumar, L. S., Takahashi, H., Talantova, M., Shin, Y., Cui, J., Tu, S., Severino, K. A., Nakanishi, N., Tong, G., Lipton, S. A., and Zhang, D. (2002). Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415, 793–798.
- 42 Wollmuth, L. P., and Sobolevsky, A. I. (2004). Structure and function of the glutamate receptor ion channel. Trends Neurosci. 27, 321–328.
- 43 Hollmann, M., and Heinemann, S. (1994). Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108.
- 44
Petralia, R. S.,
Rubio, M. E., and
Wenthold, R. J.
(1999).
Cellular and subcellular distribution of glutamate receptors.
In Ionotropic Glutamate Receptors in the CNS,
P. Jonas and
H. Monya, Eds.
Springer-Verlag, Berlin,
pp. 143–171.
10.1007/978-3-662-08022-1_4 Google Scholar
- 45 Buller, A. L., Larson, H. C., Schneider, B. E., Beaton, J. A., Morrisett, R. A., and Monaghan, D. T. (1994). The molecular basis of NMDA receptor subtypes: Native receptor diversity is predicted by subunit composition. J. Neurosci. 14, 5471–5484.
- 46 Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B., and Seeburg, P. H. (1994). Development and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12, 529–540.
- 47 Monaghan, D. T., and Beaton, J. A. (1992). Pharmacologically-distinct NMDA receptor populations of the cerebellum, medial thalamic nuclei, and forebrain. Mol. Neuropharmacol. 2, 71–75.
- 48 Buller, A. L., and Monaghan, D. T. (1997). Pharmacological heterogeneity of NMDA receptors: Characterization of NR1a/NR2D heteromers expressed in Xenopus oocytes. Eur. J. Pharmacol. 320, 87–94.
- 49 Feng, B., Tse, H. W., Skifter, D. A., Morley, R. M., Jane, D. E., and Monaghan, D. T. (2004). NMDA receptor subtype selectivity of (2R*,3R*)-1-(biphenyl-4-carbonyl)piperazine-2,3-dicarboxylic acid derivatives. Br. J. Pharmacol. 141, 508–516.
- 50 Akazawa, C., Shigemoto, R., Bessho, Y., Nakanishi, S., and Mizuno, N. (1994). Differential expression of five NMDA receptor subunit mRNAs in the cerebellum of developing and adult rats. J. Comp. Neurol. 347, 150–160.
- 51
Watanabe, M.
(1997).
Developmental dynamics of gene expression for NMDA receptor channel.
In The Ionotropic Glutamate Receptors,
D. T. Monaghan and
R. J. Wenthold, Eds.
Humana, Totowa, NJ,
pp. 189–218.
10.1007/978-1-4612-3962-8_8 Google Scholar
- 52 Ciabarra, A. M., Sullivan, J. M., Gahn, L. G., Pecht, G., Heinemann, S., and Sevarino, K. A. (1995). Cloning and characterization of χ-1: A developmentally regulated member of a novel class of the ionotropic glutamate receptor family. J. Neurosci. 15, 6498–6508.
- 53 Sucher, N. J., Akbarian, S., Chi, C. L., Leclerc, C. L., Awobuluyi, M., Deitcher, D. L., Wu, M. K., Yuan, J. P., Jones, E. G., and Lipton, S. A. (1995). Developmental and regional expression pattern of a novel NMDA receptor-like subunit (NMDAR-L) in the rodent brain. J. Neurosci. 15, 6509–6520.
- 54 Keinanen, K., Wisden, W., Sommer, B., Werner, P., Herb, A., Verdoorn, T. A., Sakmann, B., and Seeburg, P. H. (1990). A family of AMPA-selective glutamate receptors. Science 249, 556–560.
- 55 Armstrong, N., and Gouaux, E. (2000). Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: Crystal structures of the GluR2 ligand binding core. Neuron 28, 165–181.
- 56 Rosenmund, C., Stern-Bach, Y., and Stevens, C. F. (1998). The tetrameric structure of a glutamate receptor channel. Science 280, 1596–1599.
- 57 Hume, R. I., Dingledine, R., and Heinemann, S. F. (1991). Identification of a site in glutamate receptor subunits that controls calcium permeability. Science 253, 1028–1031.
- 58 Washburn, M. S., Numberger, M., Zhang, S., and Dingledine, R. (1997). Differential dependence on GluR2 expression of three characteristic features of AMPA receptors. J. Neurosci. 17, 9393–9406.
- 59 Lomeli, H., Mosbacher, J., Melcher, T., Hoger, T., Geiger, J. R., Kuner, T., Monyer, H., Higuchi, M., Bach, A., and Seeburg, P. H. (1994). Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science 266, 1709–1713.
- 60 Sommer, B., Keinänen, K., Verdoorn, T. A., Wisden, W., Burnashev, N., Herb, A., Köhler, M., Takagi, T., Sakmann, B., and Seeburg, P. H. (1990). Flip and flop: A cell-specific functional switch in glutamate-operated channels of the CNS. Science 249, 1580–1585.
- 61 Mosbacher, J., Schoepfer, R., Moyer, H., Burnashev, N., Seeburg, P., and Ruppersberg, J. (1994). A molecular determinant for submillisecond desensitization in glutamate receptors. Science 266, 1059–1062.
- 62 Quirk, J. C., Siuda, E. R., and Nisenbaum, E. S. (2004). Molecular determinants responsible for differences in desensitization kinetics of AMPA receptor splice variants. J. Neurosci. 24, 11416–11420.
- 63 Partin, K. M., Patneau, D. K., and Mayer, M. L. (1994). Cyclothiazide differentially modulates desensitization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor splice variants. Mol. Pharmacol. 46, 129–138.
- 64 Sun, Y., Olson, R., Horning, M., Armstrong, N., Mayer, M., and Gouaux, E. (2002). Mechanism of glutamate receptor desensitisation. Nature 417, 245–253.
- 65 Monaghan, D. T., Yao, D., and Cotman, C. W. (1984). Distribution of [3H]AMPA binding sites in rat brain as determined by quantitative autoradiography. Brain Res. 324, 160–164.
- 66 Nielsen, E. Ø., Drejer, J., Cha, J. H., Young, A. B., and Honoré, T. (1990). Autoradiographic characterization and localization of quisqualate binding sites in rat brain using the antagonist [3H]6-cyano-7-nitroquinoxaline-2,3-dione: Comparison with (R,S)-[3H]α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid binding sites. J. Neurochem. 54, 686–695.
- 67 Hawkins, L. M., Beaver, K. M., Jane, D. E., Taylor, P. M., Sunter, D. C., and Roberts, P. J. (1995). Characterization of the pharmacology and regional distribution of (S)-[3H]-5-fluorowillardiine binding in rat brain. Br. J. Pharmac. 116(3), 2033–2039. Erratum 116(8), 3344.
- 68 Nielsen, E. Ø., Johansen, T. H., Watjen, F., and Drejer, J. (1995). Characterization of the binding of [3H]NS 257, a novel competitive AMPA receptor antagonist, to rat brain membranes and brain sections. J. Neurochem. 65, 1264–1273.
- 69 Dev, K. K., Petersen, V., Honoré, T., and Henley, J. M. (1996). Pharmacology and regional distribution of the binding of 6-[3H] nitro-7-sulphamoylbenzo [f]-quinoxaline-2,3-dione to rat brain. J. Neurochem. 67, 2609–2612.
- 70 Mutel, V., Trube, G., Klingelschmidt, A., Messer, J., Bleuel, Z., Humbel, U., Clifford, M. M., Ellis, G. J., and Richards, J. G. (1998). Binding characteristics of a potent AMPA receptor antagonist [3H]Ro 48-8587 in rat brain. J. Neurochem. 71, 418–442.
- 71 Huettner, J. E. (2003). Kainate receptors and synaptic transmission. Prog. Neurobiol. 70, 387–407.
- 72 Lerma, J. (2003). Roles and rules of kainate receptors in synaptic transmission. Nat. Rev. Neurosci. 4, 481–495.
- 73 Agrawal, S. G., and Evans, R. H. (1986). The primary afferent depolarizing action of kainate in the rat. Br. J. Pharmacol. 87, 345–355.
- 74 Partin, K. M., Patneau, D. K., Winters, C. A., Mayer, M. L., and Buonanno, A. (1993). Selective modulation of desensitization at AMPA versus kainate receptors by cyclothiazide and concanavalin A. Neuron 11, 1069–1082.
- 75 Li, P., Wilding, T. J., Kim, S. J., Calejesan, A. A., Huettner, J. E., and Zhuo, M. (1999). Kainate-receptor-mediated sensory synaptic transmission in mammalian spinal cord. Nature 397, 161–164.
- 76 Kerchner, G. A., Wilding, T. J., Li, P., Wang, G. D., Zhuo, M., and Huettner, J. E. (2001). Presynaptic kainate receptors regulate spinal sensory transmission. J. Neurosci. 21, 59–66.
- 77 Wilding, T. J., and Huettner, J. E. (2001). Functional diversity and developmental changes in neuronal kainate receptors. J. Physiol. 532, 411–421.
- 78
Bischoff, S.,
Barhanin, J.,
Bettler, B.,
Mulle, C., and
Heinemann, S.
(1997).
Spatial distribution of kainate receptor subunit mRNA in the mouse basal ganglia and ventral mesencephalon.
J. Comp. Neurol.
379,
541–562.
10.1002/(SICI)1096-9861(19970324)379:4<541::AID-CNE6>3.0.CO;2-2 CAS PubMed Web of Science® Google Scholar
- 79 Li, H., Chen, A., Xing, G., Wei, M.-L., and Rogawski, M. A. (2001). Kainate receptor-mediated heterosynaptic facilitation in the amygdala. Nat. Neurosci. 4, 612–620.
- 80
Muñoz, A.,
Woods, T. M., and
Jones, E. G.
(1999).
Laminar and cellular distribution of AMPA, kainate, and NMDA receptor subunits in monkey sensory-motor cortex.
J. Comp. Neurol.
407,
472–490.
10.1002/(SICI)1096-9861(19990517)407:4<472::AID-CNE2>3.0.CO;2-2 CAS PubMed Web of Science® Google Scholar
- 81 Kieval, J. Z., Hubert, G. W., Charara, A., Paré, J.-F., and Smith, Y. (2001). Subcellular and subsynaptic localization of presynaptic and postsynaptic kainate receptor subunits in the monkey striatum. J. Neurosci. 21, 8746–8757.
- 82 Darstein, M., Petralia, R. S., Swanson, G. T., Wenthold, R. J., and Heinemann, S. F. (2003). Distribution of kainate receptor subunits at hippocampal mossy fiber synapses. J. Neurosci. 23, 8013–8019.
- 83 Jaskolski, F., Coussen, F., and Mulle, C. (2005). Subcellular localization and trafficking of kainate receptors. Trends Pharmacol. Sci. 26, 20–26.
- 84 Eyigor, O., Minbay, Z., Cavusoglu, I., and Jennes, L. (2005). Localization of kainate receptor subunit GluR5-immunoreactive cells in rat hypothalmus. Mol. Brain Res. 136, 38–44.
- 85 Wisden, W., and Seeburg, P. H. (1993). A complex mosaic of high-affinity kainate receptors in rat brain. J. Neurosci. 13, 3582–3598.
- 86 Belcher, S. M., and Howe, J. R. (1997). Characterization of RNA editing of the glutamate-receptor subunits GluR5 and GluR6 in granule cells during cerebellar development. Mol. Brain Res. 52, 130–138.
- 87 Delaney, A. J., and Jahr, C. E. (2002). Kainate receptors differentially regulate release at two parallel fiber synapses. Neuron 36, 475–482.
- 88 Grünert, U., Haverkamp, S., Fletcher, E. L., and Wässle, H. (2002). Synaptic distribution of ionotropic glutamate receptors in the inner plexiform layer of the primate retina. J. Comp. Neurol. 447, 138–151.
- 89 Nadler, J. (1978). Intraventricular kainic acid preferentially destroys hippocampal pyramidal cells. Nature 271, 676–677.
- 90 Ben-Ari, Y. (1985). Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14, 375–403.
- 91 Mulle, C., Sailer, A., Peréz-Otaño, I., Dickinson-Anson, H., Castillo, P. E., Bureau, I., Maron, C., Gage, F., Mann, J. R., Bettler, B., and Heinemann, S. F. (1998). Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice. Nature 392, 601–605.
- 92 Smolders, I., Bortolotto, Z. A., Clarke, V. R., Warre, R., Khan, G. M., O'Neill, M. J., Ornstein, P. L., Bleakman, D., Ogden, A. M., Weiss, B., Stables, J., Ho, K. H., Ebinger, G., Collingridge, G. L., Lodge, D., and Michotte, Y. (2002). Antagonists of GLUK5-containing kainate receptors prevent pilocarpine-induced limbic seizures. Nat. Neurosci. 5, 796–804.
- 93 Benvenga, M. J., Ornstein, P. L., and Leander, J. D. (1995). Schedule-controlled behavioral effects of the selective 2-amino-3-(5-methyl-3-hydroxyisazole-4-yl)propanoic acid antagonist LY293558 in pigeons. J. Pharmacol. Exp. Ther. 175, 164–170.
- 94 Alt, A., Weiss, B., Ogden, A. M., Gleason, S. D., Calligaro, D. O., Bleakman, D., and Witkin, J. M. (2006). In vitro and in vivo studies in rats with LY293558 suggest AMPA/kainate receptor blockade as a novel potential mechanism for the therapeutic treatment of anxiety disorders. Psychopharmacology 185, 24–247.
- 95 Schoepp, D. D., Lodge, D., Bleakman, D., Leander, J. D., Tizzano, J. P., Wright, R. A., Palmer, A. J., Salhoff, C. R., and Ornstein, P. L. (1995). In vitro and in vivo antagonism of AMPA receptor activation by (3S, 4aR, 6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl] decahydroisoquinoline-3-carboxylic acid. Neuropharmacology 34, 1159–1168.
- 96 Bleakman, D., Schoepp, D. D., Ballyk, B., Bufton, H., Sharpe, E. F., Thomas, K., Ornstein, P. L., and Kamboj, R. K. (1996). Pharmacological discrimination of GluR5 and GluR6 kainate receptor subtypes by (3S, 4aR, 6R, 8aR)-6-[2-(1 (2) H-tetrazole-5-yl)ethyl] decahydroisoquinoline-3 carboxylic acid. Mol. Pharmacol. 49, 581–585.
- 97 Alt, A., Weiss, B., Ogden, A. M., Knauss, J. L., Oler, J., Ho, K., Large, T. H., and Bleakman, D. (2004). Pharmacological characterization of glutamatergic agonists and antagonists at recombinant human homomeric and heteromeric kainate receptors in vitro. Neuropharmacology 46, 793–806.
- 98 Simmons, R. M. A., Li, D. L., Hoo, K. H., Deverill, M., Ornstein, P. L., and Iyengar, S. (1998). Kainate GluR5 receptor subtype mediates the nociceptive response to formalin in the rat. Neuropharmacology 37, 25–36.
- 99 Filla, S. A., Winter, M. A., Johnson, K. W., Bleakman, D., Bell, M. G., Bleisch, T. J., Castaño, A. M., Clemens-Smith, A., del Prado, M., Dieckman, D. K., Dominguez, E., Escribano, A., Hoo, K. H., Hudziak, K. J., Katofiasc, M. A., Martinez-Perez, J. A., Mateo, A., Mathes, B. M., Mattiuz, E. L., Ogden, A. M. L., Phebus, L. A., Stack, D. R., Stratford, R. E., and Ornstein, P. L. (2002). Ethyl (3S,4aR,6S8aR)-6-(4-ethoxycarbonylimidazol-1-ylmethyl)decahydroisoquinoline-3-carboxylic ester: A prodrug of a GluR5 KA receptor antagonist active in two animal models of acute migraine. J. Med. Chem. 45, 4383–4386.
- 100 Palecek, J., Neugebauer, V., Carlton, S. M., Iyengar, S., and Willis, W. D. (2004). The effect of a kainate GluR5 receptor antagonist on responses of spinothalamic tract neurons in a model of peripheral neuropathy in primates. Pain 111, 10151–10161.
- 101 Dominguez, A., Iyengar, S., Shannon, H. E., Bleakman, D., Alt, A., Arnold, B. M., Bell, M. G., Bleisch, T. J., Buckmaster, J. L., Castano, A. M., Del Prado, M., Escribano, A., Filla, S. A., Ho, K. H., Hudziak, K. J., Jones, C. K., Martinez-Perez, J. A., Mateo, A., Mathes, B. M., Mattiuz, E. L., Ogden, A. M. L., Simmons, R. M., Stack, D. R., Stratford, R. E., Winter, M. A., Wu, Z., and Ornstein, P. L. (2005). Two prodrugs of potent and selective GluR5 kainate receptor antagonists actives in three animal models of pain. J. Med. Chem. 48, 4200–4203.
- 102 Sang, C. N., Hostetter, M. P., Gracely, R. H., Chappell, A. S., Schoepp, D. D., Lee, G., Whitcup, S., Caruso, R., and Max, M. B. (1998). AMPA/kainate antagonist LY293558 reduces capsaicin-evoked hyperalgesia but not pain in normal skin in humans. Anesthesiology 89, 1060–1067.
- 103 Gilron, I., Max, M. B., Lee, G., Booher, S. L., Sang, C. N., Chappell, A. S., and Dionne, R. A. (2000). Effects of the 2-amino-3-hydroxy-5-methyl-4-isoxazole-propanoic acid/kainate antagonist LY293558 on spontaneous and evoked postoperative pain. Clin. Pharmacol. Ther. 68, 320–327.
- 104 Sang, C. N., Ramadan, N. M., Wallihan, R. G., Chappell, A. S., Freitag, F. G., Smith, T. R., Silberstein, S. D., Johnson, K. W., Phebus, L. A., Bleakman, D., Ornstein, P. L., Arnold, B., Tepper, S. J., and Vandenhende, F. (2004). LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine. Cephalalgia 24, 596–602.
- 105 Sahara, Y., Noro, N., Lida, Y., Soma, Y., and Nakamura, Y. (1997). Glutamate receptor subunits GluR5 and KA-2 are coexpressed in rat trigeminal ganglion neurons. J. Neurosci. 17, 6611–6620.
- 106 Curtis, D. R., Lodge, D., and McLennan, H. (1979). The excitation and depression of spinal neurones by ibotenic acid. J. Physiol. 291, 19–28.
- 107 Schoepp, D. D., Smith, C. L., Lodge, D., Millar, J. D., Leander, J. D., Sacaan, A. I., and Lunn, W. H. W. (1991). d,l-Tetrazol-5-ylglycine: A novel and highly potent NMDA receptor agonist. Eur. J. Pharmacol. 203, 237–243.
- 108 Lunn, W. H. W., Schoepp, D. D., Calligaro, D. O., Vasileff, R. T., Heinz, L. J., Salhoff, C. R., and O'Malley, P. J. (1992). d,l-Tetrazol-5-ylglycine, a highly potent NMDA agonist: Its synthesis and NMDA receptor efficacy. J. Med. Chem. 35, 4608–4612.
- 109 Monahan, J. B., Hood, W. F., Compton, R. P., Cordi, A. A., Snyder, J. P., Pellicciari, R., and Natalina, B. (1990). Characterisation of d-3,4-cyclopropylglutamates as N-methyl-d-aspartate receptor agonists. Neurosci. Lett. 112, 328–332.
- 110 Allan, R. D., Hanrahan, J. R., Hambley, T. W., Johnston, G. A. R., Mewett, K. N., and Mitrovic, A. D. (1990). 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. 33, 2905–2915.
- 111 Grimwood, S., Wafford, K. A., MacCaulay, A., and Hutson, P. H. (2002). N-Methyl-d-aspartate receptor subtype-selectivity of homoquinolinate: An electrophysiological and radioligand binding study using both native and recombinant receptors. J. Neurochem. 82, 794–800.
- 112 Morris, R. G. M., Anderson, E., Lynch, G. S., and Baudry, J. N. P. (1986). Selective impairment and blockade of long-term potentiation by an N-methyl-d-aspartate receptor antagonist, AP5. Nature 297, 681–683.
- 113 Simon, R. P., Swan, J. H., Griffiths, T., and Meldrum, B. S. (1984). Blockade of N-methyl-d-aspartate receptors may protect against ischemic damage in the brain. Science 226, 850–852.
- 114 Jane, D. E., Olverman, H. J., and Watkins, J. C. (1994). Agonists and competitive antagonists: Structure-activity and molecular modelling studies. In The NMDA Receptor, 2nd ed., G. L. Collingridge and J. C. Watkins, Eds. Oxford University Press, Oxford, pp. 31–104.
- 115 Johnson, G., and Ornstein, P. L. (1996). Competitive NMDA antagonists—A comprehensive analysis of molecular biological, structure activity and molecular modelling relationships. Curr. Pharm. Des. 2, 331–356.
- 116 Fagg, G. E., Olpe, H. R., Pozza, M. F., Baud, J., Steinmann, M., Schmutz, M., Portet, C., Baumann, P., Thedinga, K., Bittiger, H., Allgeier, H., Heckendorn, R., Angst, C., Brundish, D., and Dingwall, J. G. (1990). CGP 37849 and CGP 39551: Novel and competitive N-methyl-d-aspartate receptor antagonists with oral activity. Br. J. Pharmacol. 99, 791–797.
- 117 Whitten, J. P., Baron, B. M., Miller, D. M. F., White, H. S., and McDonald, I. A. (1990). (R)-4-Oxo-5-phosphononorvaline: A new competitive glutamate antagonist at the NMDA receptor complex. J. Med. Chem. 33, 2961–2963.
- 118 Ornstein, P. L., Arnold, M. B., Lunn, W. H. W., Heinz, L. J., Leander, J. D., Lodge, D., and Schoepp, D. D. (1998). Heteroatom-substitution as a strategy for increasing the potency of competitive NMDA antagonists. Bioorg. Med. Chem. Lett. 8, 389–394.
- 119 Hutchison, A. J., Williams, M., Angst, C., de Jesus, R., Blanchard, L., Jackson, R. H., Wilusz, E. J., Murphy, D. E., Bernard, P. S., Schneider, J., Campbell, T., Guida, W., and Sills, M. A. (1989). 4-(Phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids: Synthesis, activity at N-methyl-d-aspartic acid receptors, and anticonvulsant activity. J. Med. Chem. 32, 2171–2178.
- 120 Davies, J., Evans, R. H., Herrling, P. L., Jones, A. W., Olverman, H. J., Pook, P., and Watkins, J. C. (1986). CPP a new and selective NMDA antagonist. Depression of central neuron responses, affinity for [3H]D-AP5 binding sites on brain membranes and anticonvulsant activity. Brain Res. 382, 169–173.
- 121 Aebischer, B., Frey, P., Haerter, H. P., Herrling, P. L., Mueller, W. A., Olverman, H. J., and Watkins, J. C. (1989). Synthesis and NMDA antagonist properties of the enantiomers of 4-(3-phosphonopropyl)piperazine-2-carboxylic acid (CPP) and of the unsaturated analogue (E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (CPP-ene). Helv. Chim. Acta 72, 1043–1051.
- 122 Whitten, J. P., Muench, D., Cube, R. V., Nyce, P. L., Baron, B. M., and McDonald, I. A. (1991). Synthesis of 3(S)-phosphonoacetyl-2(R)-piperidine-carboxylic acid, a conformationally restricted glutamate antagonist. Bioorg. Med. Chem. Lett. 1, 441–444.
- 123 Ornstein, P. L., and Klimkowski, V. J. (1992). Competitive NMDA receptor antagonists. In Excitatory Amino Acid Receptors. Design of Agonists and Antagonists. Ellis Horwood, Chichester, pp. 183–201.
- 124 Ornstein, P. L., Schoepp, D. D., Arnold, M. B., Augenstein, N. K., Lodge, D., Millar, J. D., Chambers, J., Campbell, J., Paschal, J. W., Zimmerman, D. M., and Leander, J. D. (1992). 6-Substituted decahydroisoquinoline-3-carboxylic acids as potent and selective conformationally constrained NMDA receptor antagonists. J. Med. Chem. 35, 3547–3560.
- 125 Herrling, P. L. (1997). Excitatory Amino Acids—Clinical Results with Antagonists. Academic, London.
- 126 Feng, B., Morley, R. M., Jane, D. E., and Monaghan, D. T. (2005). The effect of competitive antagonist chain-length on NMDA receptor subunit selectivity. Neuropharmacology 48, 354–359.
- 127 Auberson, Y. P., Allgeier, H., Bischoff, S., Lingenhoehl, K., Moretti, R., and Schmutz, M. (2002). 5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for human 1A/2A, rather than 1A/2B receptor composition. Bioorg. Med. Chem. Lett. 12, 1099–1102.
- 128 Weitlauf, C., Honse, Y., Auberson, Y. P., Mishina, M., Lovinger, D. M., and Winder, D. G. (2005). Activation of NR2A-containing NMDA receptors is not obligatory for NMDA receptor-dependent long-term potentiation. J. Neurosci. 25, 8386–8390.
- 129 Morley, R. M., Tse, H.-W., Feng, B., Miller, J. C., Monaghan, D. T., and Jane, D. E. (2005). Synthesis and pharmacology of N1-substituted piperazine-2,3-dicarboxylic acid derivatives acting as NMDA receptor antagonists. J. Med. Chem. 48, 2627–2637.
- 130 Donevan, S. D., and McCabe, R. T. (2000). Conantokin G is an NR2B selective competitive antagonist of N-methyl-d-aspartate receptors. Mol. Pharmacol. 58, 614–623.
- 131 Stensbol, T. B., Madsen, U., and Krogsgaard-Larsen, P. (2002). The AMPA receptor binding site: Focus on agonists and competitive antagonists. Curr. Pharm. Des. 8, 857–872.
- 132 Brauner-Osborne, H., Egebjerg, J., Nielsen, E. O., Madsen, U., and Krogsgaard-Larsen, P. (2000). Ligands for glutamate receptors: Design and therapeutic prospects. J. Med. Chem. 43, 2609–2645.
- 133 Wahl, P., Madsen, U., Banke, T., Krogsgaard-Larsen, P., and Schousboe, A. (1996). Different characteristics of AMPA receptor agonists acting at AMPA receptors expressed in Xenopus oocytes. Eur. J. Pharmacol. 308, 211–218.
- 134 Krogsgaard-Larsen, P., Nielsen, E. O., and Curtis, D. R. (1984). Ibotenic acid analogues. Synthesis and biological and in vitro activity of conformationally restricted agonists at central excitatory amino acid receptors. J. Med. Chem. 5, 585–591.
- 135 Wong, L. A., Mayer, M. L., Jane, D. E., and Watkins, J. C. (1994). Willardiines differentiate agonist binding sites for kainate-versus AMPA preferring glutamate receptors in DRG and hippocampal neurons. J. Neurosci. 14, 3881–3897.
- 136 Zaczek, R., and Coyle, J. T. (1982). Excitatory amino acid analogues: Neurotoxicity and seizures. Neuropharmacology 21, 15–26.
- 137 Kiskin, N. I., Krishtal, O. A., and Tsyndrenko, A. Y. (1986). Excitatory amino acid receptors in hippocampal neurons: Kainate fails to desensitize them. Neurosci. Lett. 63, 225–230.
- 138 Patneau, D. K., Vyklicky, L., Jr., and Mayer, M. L. (1993). Hippocampal neurons exhibit cyclothiazide-sensitive rapidly desensitizing responses to kainate. J. Neurosci. 13, 3496–3509.
- 139 Trussell, L. O., Thio, L. L., Zorumski, C. F., and Fischbach, G. D. (1988). Rapid desensitization of glutamate receptors in vertebrate central neurons. Proc. Nat. Acad. Sci. 85, 4562–4566.
- 140 Koike, M., Tsukada, S., Tsuzuki, K., Kijima, H., and Ozawa, S. (2000). Regulation of kinetic properties of GluR2 AMPA receptor channels by alternative splicing. J. Neurosci. 20, 2166–2174.
- 141 Mayer, M. L., and Vyklicky, L., Jr. (1989). The action of zinc on synaptic transmission and neuronal excitability in cultures of mouse hippocampus. J. Physiol.-Lond. 415, 351–365.
- 142 Swanson, G. T., Kamboj, S. K., and Cull-Candy, S. G. (1997). Single channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition. J. Neurosci. 17, 58–69.
- 143 Drejer, J., and Honoré, T. (1988). New quinoxalinediones show potent antagonism of quisqualate responses in cultured mouse cortical neurons. Neurosci. Lett. 87, 104–108.
- 144 Fletcher, E. J., Martin, D., Aram, J. A., Lodge, D., and Honoré, T. (1988). Quinoxalinediones selectively block quisqualate and kainate receptors and synaptic events in rat neocortex and hippocampus and frog spinal cord in vitro. Br. J. Pharmacol. 95, 585–597.
- 145 Birch, P. J., Grossman, C. J., and Hayes, A. G. (1988). 6,7-Dinitro-quinoxaline-2,3-dion and 6-nitro,7-cyano-quinoxaline-2,3-dion antagonise responses to NMDA in the rat spinal cord via an action at the strychnine-insensitive glycine receptor. Eur. J. Pharmacol. 156, 177–180.
- 146 Sheardown, M. J., Nielsen, E. Ø., Hansen, A. J., Jacobsen, P., and Honoré, T. (1990). 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline: A neuroprotectant for cerebral ischemia. Science 247, 571–574.
- 147 Ohmori, J., Sakamoto, S., Kubota, H., Shimizu-Sasamata, M., Okada, M., Kawasak, S., Hidaka, K., Togami, J., Furuya, T., and Murase, K. (1994). 6-(1H-Imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K) and related compounds: Structure–activity relationships for the AMPA-type non-NMDA receptor. J. Med. Chem. 37, 467–475.
- 148 Kohara, A., Okada, M., Tsutsumi, R., Ohno, K., Takahashi, M., Shimizu-Sasamata, M., Shishikura, J., Inami, H., Sakamoto, S., and Yamaguchi, T. (1998). In-vitro characterization of YM872, a selective, potent and highly water-soluble alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist. J. Pharm. Pharmacol. 50, 795–801.
- 149 Turski, L., Huth, A., Sheardown, M., McDonald, F., Neuhaus, R., Schneider, H. H., Dirnagl, U., Wiegand, F., Jacobsen, P., and Ottow, E. (1998). ZK200775: A phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma. Proc. Nat. Acad. Sci. 95, 10960–10965.
- 150 Bleakman, D., and Lodge, D. (1998). Neuropharmacology of AMPA and kainite receptors. Neuropharmacology 37, 1187–1204.
- 151 Ornstein, P. L., Arnold, M. B., Augenstein, N. K., Lodge, D., Leander, J. D., and Schoepp, D. D. (1993). (3SR,4aRS,6RS,8aRS)-6-[2-(1H-tetrazol-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid: A structurally novel, systemically active, competitive AMPA receptor antagonist. J. Med. Chem. 36, 2046–2048.
- 152 Clarke, V. R. J., Ballyk, B. A., Hoo, K. H., Mandelzys, A., Pellizzari, A., Bath, C. P., Thomas, J., Sharpe, E. F., Davies, C. H., Ornstein, P. L., Schoepp, D. D., Kamboj, R. K., Collingridge, G. L., Lodge, D., and Bleakman, D. (1997). A hippocampal GluR5 kainate receptor regulating inhibitory synaptic transmission. Nature 389, 599–603.
- 153 O'Neill, M. J., Bond, A., Ornstein, P. L., Ward, M. A., Hicks, C. A., Hoo, K., Bleakman, D., and Lodge, D. (1998). Decahydroisoquinolines: Novel competitive AMPA/kainate antagonists with neuroprotective effects in global cerebral ischaemia. Neuropharmacology 37, 1211–1222.
- 154 Schiffer, H. H., Swanson, G. T., and Heinemann, S. F. (1997). Rat GluR7 and a carboxy-terminal splice variant, GluR7b, are functional kainate receptor subunits with a low sensitivity to glutamate. Neuron 19, 1141–1146.
- 155 Sutton, J. L., Maccecchini, M. L., and Kajander, K. C. (1999). The kainate receptor antagonist 2S,4R-4-methylglutamate attenuates mechanical allodynia and thermal hyperalgesia in a rat model of nerve injury. Neuroscience 91, 283–292.
- 156 Small, B., Thomas, J., Kemp, M., Hoo, K., Ballyk, B., Deverill, M., Ogden, A. M., Rubio, A., Pedregal, C., and Bleakman, D. (1998). LY339434, a GluR5 kainate receptor agonist. Neuropharmacology 37, 1261–1267.
- 157 Baker, S. R., Bleakman, D., Ezquerra, J., Ballyk, B. A., Deverill, M., Ho, K., Kamboj, R. K., Collado, I., Domínguez, C., Escribano, A., Mateo, A. I., Pedregal, C., and Rubio, A. (2000). 4-Alkylidenyl glutamic acids, potent and selective GluR5 antagonists. Bioorg. Med. Chem. Lett. 10, 1807–1810.
- 158 Bleakman, D., Ogden, A. M., Ornstein, P. L., and Hoo, K. (1999). Pharmacological characterization of a GluR6 kainate receptor in cultured hippocampal neurons. Eur. J. Pharmacol. 378, 331–337.
- 159 Bureau, I., Bischoff, S., Heinemann, S. F., and Mulle, C. (1999). Kainate receptor-mediated responses in the CA1 field of wild-type and GluR6-deficient mice. J. Neurosci. 19, 635–663.
- 160 Christensen, J. K., Varming, T., Ahring, P. K., Jørgensen, T. D., and Nielsen, E. Ø. (2004). In vitro characterization of 5-carboxyl-2,4-di-benzamido-benzoic acid (NS3763), a noncompetitive antagonist of GLUK5 receptors. J. Pharmacol. Exp. Ther. 309, 1003–1010.
- 161 Sakai, R., Kamiya, H., Murata, M., and Shimamoto, K. (1997). Dysiherbaine: A new neurotoxic amino acid from the Micronesian marine sponge, Dysidea herbacea. J. Am. Chem. Soci. 119, 4112–4116.
- 162 Sakai, R., Swanson, G. T., Shimamoto, K., Green, T., Contractor, A., Ghetti, A., Tamura-Horikawa, Y., Oiwa, C., and Kamiya, H. (2001). Pharmacological properties of the potent epileptogenic amino acid dysiherbaine, a novel glutamate receptor agonist isolated from the marine sponge Dysidea herbacea. J. Pharmacol. Exp. Ther. 296, 650–658.
- 163 Sanders, J. M., Ito, K., Settimo, L., Pentikäinen, O. T., Shoji, M., Sasaki, M., Johnson, M. S., Sakai, R., and Swanson, G. T. (2005). Divergent pharmacological activity of novel marine-derived excitatory amino acids on glutamate receptors. J. Pharmacol. Exp. Ther. 314, 1068–1078.
- 164 Swanson, G. T., Green, T., Sakai, R., Contractor, A., Che, W., Kamiya, H., and Heinemann, S. F. (2002). Differential activation of individual subunits in heteromeric kainate receptors. Neuron 34, 589–598.
- 165 Sakai, R., Koike, T., Sasaki, M., Shimamoto, K., Oiwa, C., Yano, A., Suzuki, K., Tachibana, K., and Kamiya, H. (2001). Isolation, structure determination, and synthesis of neodysiherbaine A, a new excitatory amino acid from a marine sponge. Organ. Lett. 3, 1479–1482.
- 166 Gmelin, R. (1961). Isolierung von willardiine (3-(1-uracil)-l-alanin) aus den samen von Acacia millefolia Acacia lemmoni und Mimosa asperata. Acta Chem. Scandi. 15, 1188–1189.
- 167 Patneau, D. K., Mayer, M. L., Jane, D. E., and Watkins, J. C. (1992). Activation and desensitization of AMPA/kainate receptors by novel derivatives of willardiine. J. Neurosci. 12, 595–606.
- 168 Jane, D. E., Hoo, K., Kamboj, R., Deverill, M., Bleakman, D., and Mandelzys, A. (1997). Synthesis of willardiine and 6-azawillardiine analogs: Pharmacological characterization on cloned homomeric human AMPA and kainate receptor subtypes. J. Med. Chem. 40, 3645–3650.
- 169 Swanson, G. T., Green, T., and Heinemann, S. F. (1998). Kainate receptors exhibit differential sensitivities to (S)-5-iodowillardiine. Mol. Pharmacol. 53, 942–949.
- 170 Lauridsen, J., Honoré, T., and Krogsgaard-Larsen, P. (1985). Ibotenic acid analogues. Synthesis, molecular flexibility, and in vitro activity of agonists and antagonists at central glutamic acid receptors. J. Med. Chem. 28, 668–672.
- 171 Verdoorn, T. A., Johansen, T. H., Drejer, J., and Nielsen, E. O. (1994). Selective block of recombinant glur6 receptors by NS-102, a novel non-NMDA receptor antagonist. Eur. J. Pharmacol. 269, 43–49.
- 172 Wilding, T. J., and Heuttner, J. E. (1996). Antagonist pharmacology of kainate- and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-preferring receptors. Mol. Pharmacol. 49, 540–546.
- 173 Blackburn-Munro, G. B., Bomholt, S. F., and Erichsen, H. K. (2004). Behavioural effects of the novel AMPA/GluR5 selective receptor antagonist NS1209 after systemic administration in animal models of experimental pain. Neuropharmacology 47, 351–362.
- 174 Nielsen, E. Ø., Varming, T., Mathiesen, C., Jensen, L., Møller, A., Gouliaev, A. H., Wätjen, F., and Drejer, J. (1999). SPD 502: A water-soluble and in vivo long-lasting AMPA antagonist with neuroprotective activity. J. Pharmacol. Exper. Ther. 289, 1492–1501.
- 175 Wilding, T. J., and Huettner, J. E. (1995). Differential antagonism of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-preferring and kainate-preferring receptors by 2,3-benzodiazepines. Mol. Pharmacol. 47, 582–587.
- 176 Lufty, K., Woodward, R. M., Keana, J. F. W., and Weber, E. (1994). Inhibition of clonic seizure-like excitatory effects induced by intrathecal morphine using two NMDA receptor antagonists: MK-801 and ACEA-1011. Eur. J. Pharmacol. 252, 261–266.
- 177 Woodward, R. M., Huettner, J. E., Tran, M., Guastella, J., Keana, J. F., and Weber, E. (1995). Pharmacology of 5-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione: A novel systemically active ionotropic glutamate receptor antagonist. J. Pharmacol. Exp. Ther. 275, 1209–1218.
- 178 Schoepp, D. D., Ornstein, P. L., Salhoff, C. R., and Leander, J. D. (1991). Neuroprotective effects of LY274614, a structurally novel systemically active competitive NMDA receptor antagonist. J. Neural Transmission 85, 131–143.
- 179 Bleakman, D., Gates, M. R., Ogden, A. M., and Mackowiak, M. (2002). Kainate receptor agonists, antagonists, and allosteric modulators. Curr. Pharm. Des. 8, 873–885.
- 180 Bortolotto, Z. A., Clarke, V. R. J., Delany, C. M., Parry, M. C., Smolders, I., Vignes, M., Ho, K. H., Miu, P., Brinton, B. T., Fantaske, R., Ogden, A., Gates, M., Ornstein, P. L., Lodge, D., Bleakman, D., and Collingridge, G. L. (1999). Kainate receptors are involved in synaptic plasticity. Nature 402, 297–301.
- 181 More, J. C. A., Troop, H. M., and Jane, D. E. (2002). The novel antagonist 3-CBW discriminates between kainate receptors expressed on neonatal rat motoneurones and those on dorsal root C-fibres. Br. J. Pharmacol. 137, 1125–1133.
- 182 More, J. C. A., Troop, H. M., Dolman, N. P., and Jane, D. E. (2003). Structural requirements for novel willardiine derivatives acting as AMPA and kainate receptor antagonists. Br. J. Pharmacol. 138, 1093–1100.
- 183 More, J. C. A., Nitisco, R., Dolman, N. P., Clarke, V. R. J., Alt, A. J., Ogden, A. M., Buelens, F. P., Troop, H. M., Kelland, E. E., Pilato, F., Bleakman, D., Bortolotto, Z. A., Collingridge, G. L., and Jane, D. E. (2004). Characterisation of UBP296: A novel, potent and selective kainate receptor antagonist. Neuropharmacology 47, 46–64.
- 183a Christensen, J. K., Paternain, A. V., Selak, S., Ahring, P. K. and Lerma, J. (2004). A mosaic of functional kainate receptors in hippocampal interneurons. J. Neurosci. 24, 8986–8993.
- 185 Dolman, N. P., Troop, H. M., More, J. C. A., Alt, A., Ogden, A. M., Nitisco, R. N., Jones, S. J., Buelens, F. P., Morley, R. M., Roberts, P. J., Bleakman, D., Collingridge, G. L., and Jane, D. E. (2005). Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors. J. Med. Chem. 48, 4200–4203.
- 186 Ganong, A. H., Lanthorn, T. H., and Cotman, C. W. (1983). Kynurenic acid inhibits synaptic and acidic amino acid-induced responses in the rat hippocampus and spinal cord. Brain Res. 273, 170–174.
- 187 Davies, J., and Watkins, J. C. (1985). Depressant actions of γ-d-Glutamylaminomethyl sulfonate (GAMS) on amino acid-induced and synaptic excitation in the cat spinal cord. Brain Res. 327, 113–120.
- 188 Zhou, N., and Parks, T. N. (1992). γ -d-Glutamylaminomethyl sulfonic acid (GAMS) distinguishes subtypes of glutamate receptor in the chick cochlear nucleus (nuc. magnocellularis). Hearing Res. 60, 20–26.
- 189 Zhou, N., Hammerland, L.G., and Parks, T. N. (1993). γ-d-Glutamylaminomethyl sulfonic acid (GAMS) distinguishes kainic acid- from AMPA-induced responses in Xenopus oocytes expressing chick brain receptors. Neuropharmacology 32, 767–775.
- 190 Danysz, W., and Parsons, C. G. (1998). Glycine and N-methyl-d-aspartate receptors: Physiological significance and possible therapeutic applications. Pharmacol. Rev. 50, 597–664.
- 191 Fletcher, E. J., and Lodge, D. (1988). Glycine reverses antagonism of N-methyl-d-aspartate (NMDA) by 1-hydroxy-3-aminopyrrolidone-2 (HA-966) but not by d-2-amino-5-phophonovalerate (D-AP5) on rat cortical slices. Eur. J. Pharmacol. 151, 161–162.
- 192 Leeson, P. D., and Iversen, L. L. (1994). The glycine site on the NMDA receptor: Structure-activity relationships and therapeutic potential. J. Med. Chem. 37, 4053–4067.
- 193 Watson, G. B., and Lanthorn, T. H. (1990). Pharmacological characteristics of cyclic homologues of glycine at the N-methyl-d-aspartate receptor-associated glycine site. Neuropharmacology 29, 727–730.
- 194 Rock, D. M., and Macdonald, R. L. (1995). Polyamine regulation of N-methyl-d-aspartate receptor channels. Annu. Rev. Pharmacol. Toxicol. 35, 463–482.
- 195 Durand, G. M., Benett, M. V., and Zukin, R. S. (1993). Splice variants of the N-methyl-d-aspartate receptor NR1 identify domains involved in regulation by polyamines and protein kinase C. Proc. Nat. Acad. Sci. 90, 6731–6735.
- 196 Williams, K., Zappia, A. M., Pritchett, D. B., Shen, Y. M., and Molinoff, P. B. (1994). Sensitivity of the N-methyl-d-aspartate receptor to polyamines is controlled by NR2 subunits. Mol. Pharmacol. 45, 803–809.
- 197 Harvey, S. C., and Skolnick, P. (1999). Polyamine-like actions of aminoglycosides at recombinant N-methyl-d-aspartate receptors. J. Pharmacol. Exp. Ther. 291, 285–291.
- 198 Paoletti, P., Neyton, J., and Ascher, P. (1995). Glycine-independent and subunit specific potentiation of NMDA responses by extracellular Mg2+. Neuron 15, 1109–1120.
- 199 Kew, J. N., and Kemp, J. A. (1998). Al allosteric interaction between the NMDA receptor polyamine and ifenprodil sites in rat cultured cortical neurons. J. Physiol. 512, 17–28.
- 200 Malayev, A., Gibbs, T. T., and Farb, D. H. (2002). Inhibition of the NMDA response by pregenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids. Br. J. Pharmacol. 135, 901–909.
- 201 Skolnick, P., Boje, K., Miller, R., Pennington, M., and Maccecchini, M.-L. (1992). Noncompetitive inhibition of N-methyl-d-aspartate by conantokin-G: Evidence for an allosteric interaction at polyamine sites. J. Neurochem. 59, 1516–1521.
- 202 Chandler, P., Pennington, M., Maccecchini, M. L., Nashed, N. T., and Skolnick, P. (1993). Polyamine-like action of peptides derived from conantokin-G, an N-methyl-d-aspartate (NMDA) antagonist. J. Biol. Chem. 268, 17173–17178.
- 203 Zhou, L.-M., Szendrai, G. I., Fossom, L. H., Maccecchini, M.-L., Skolnick, P., and Otvos, Jr., L. (1996). Synthetic analogues of conantokin-G: NMDA antagonists acting through a novel polyamine-coupled site. J. Neurochem. 66, 620–628.
- 204 Watson, G. B., Hood, W. F., Monahan, J. B., and Lanthorn, T. H. (1988). Kynurenate antagonizes actions of N-methyl-d-aspartate through a glycine sensitive receptor. Neurosci. Res. 2, 169–174.
- 205 Foster, A. C., and Kemp, J. A. (1989). HA-966 antagonizes N-methyl-d-aspartate receptors through a selective interaction with the glycine modulatory site. J. Neurosci. 9, 2191–2196.
- 206 Kemp, J. A., Foster, A. C., Leeson, P. D., Priestley, T., Tridgett, R., and Iversen, L. L. (1988). 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-d-aspartate receptor complex. Proc. Nat. Acad. Sci. 85, 6547–6550.
- 207 Leeson, P. D., Williams, B. J., Rowley, M., Moore, K. W., Baker, R., Kemp, J. A., Priestly, T., Foster, A. C., and Donald, E. A. (1993). Derivatives of 1-hydroxy-3-aminopyrrolidin-2-one (HA-966). Partial agonists at the glycine site of the NMDA receptor. Bioorg. Med. Chem. Lett. 3, 71–76.
- 208 Gill, R., Hargreaves, R. J., and Kemp, J. A. (1995). The neuroprotective effect of the glycine site antagonist 3R-(+)-cis-4-methyl-HA966 (L-687,414) in a rat model of focal ischaemia. J. Cereb. Blood Flow Metab. 15, 197–204.
- 209 Priestly, T., Marshall, G. R., Hill, R. G., and Kemp, J. A. (1998). L-687,414, a low efficacy NMDA receptor glycine site partial agonist in vitro, does not prevent hippocampal LTP in vivo at plasma levels known to be neuroprotective. Br. J. Pharmacol. 124, 1767–1773.
- 210 Marvizon, J. C. G., Lewin, A. H., and Skolnick, P. (1989). 1-Aminocyclopropane carboxylic acid: A potent and selective ligand for the glycine modulatory site of the N-methyl-d-aspartate receptor complex. J. Neurochem. 52, 992–994.
- 211 Hood, W. F., Sun, E. T., Compton, R. P., and Monahan, J. B. (1989). 1-Aminocyclobutane-1-carboxylate (ACBC) a specific antagonist of the N-methyl-d-aspartate receptor coupled glycine receptor. Eur. J. Pharmacol. 161, 281–282.
- 212 Hood, W. F., Compton, R. P., and Monahan, J. B. (1989). d-Cycloserine: A ligand for the N-methyl-d-aspartate coupled glycine receptor has partial agonist characteristics. Neurosci. Lett. 98, 91–95.
- 213 Birch, P. J., Grossman, C. J., and Hayes, A. G. (1988). Kynurenic acid antagonises responses to NMDA via an action at the strychnine-insensitive glycine receptor. Eur. J. Pharmacol. 154, 85–87.
- 214 Yoneda, Y., Suzuki, T., Ogita, K., and Han, D. (1993). Support for radiolabelling of a glycine recognition domain on the N-methyl-d-asparte receptor ionophore complex by 5,7-[3H]-dichloro-kynurenate in rat brain. J. Neurochem. 60, 834–635.
- 215 Honoré, T., Davies, S. N., Drejer, J., Fletcher, E. J., Jacobsen, P., Lodge, D., and Nielsen, F. E. (1988). Quinoxalinediones: Potent competitive non-N-methyl-d-aspartate glutamate receptor antagonists. Science 241, 701–703.
- 216 Birch, P. J., Grossman, C. J., and Hayes, A. G. (1988). Kynurenate and FG9041 have both competitive and non-competitive actions at excitatory amino acid receptors. Eur. J. Pharmacol. 151, 313–315.
- 217 Leeson, P. D., Carling, R. W., Moore, K. W., Moseley, A. M., Smith, J. D., Stevenson, G., Chan, T., Baker, R., Foster, A. C., Grimwood, S., Kemp, J. A., Marshall, G. R., and Hoogsteen, K. (1992). 4-Amido-2-carboxytetrahydroisoquinolines. Structure-activity relationships for antagonism of the glycine site of the NMDA receptor. J. Med. Chem. 35, 1954–1968.
- 218 Kulagowski, J. J., Baker, R., Curtis, N. R., Leeson, P. D., Mawer, I. M., Moseley, A. M., Ridgill, M. P., Rowley, M., Stansfield, I., Foster, A. C., Grimwood, S., Hill, R. G., Kemp, J. A., Marshall, G. R., Saywell, K. L., and Tricklebank, M. D. (1994). 3′-(Arylmethyl)- and 3′-(aryloxy)-3-phenyl-4-hydroxyquinolin-2(1H)-ones: Orally active antagonists of the glycine site of the NMDA receptor. J. Med. Chem. 37, 1402–1405.
- 219 Cai, S. X., Kehr, S. M., Zhou, Z.-L., Ilyin, V., Espitia, S. A., Tran, M., Hawkinson, J. E., Woodward, R. M., Weber, E., and Keana, J. F. W. (1997). Structure-activity relationships of alkyl- and alkoxy-substituted 1,4-dihydroquinoxaline-2,3-diones: Potent and systemically active antagonists for the glycine site of the NMDA receptor. J. Med. Chem. 40, 730–738.
- 220 Di Fabio, R., Capelli, A. M., Conti, N., Cugola, A., Donati, D., Feriani, A., Gastaldi, P., Gaviraghi, G., Hewkin, C. T., Micheli, F., Missio, A., Mugnaini, M., Pecunioso, A., Quaglia, A. M., Ratti, E., Rossi, L., Tedesco, G., Trist, D. G., and Reggiani, A. (1997). Substituted indole-2-carboxylates as in vivo potent antagonists acting at the strychnine-insensitive glycine binding site. J. Med. Chem. 40, 841–850.
- 221 Parsons, C. G., Danysz, W., Quack, G., Hartmann, S., Lorenz, B., Baran, L., Przegalinski, E., Kostowski, W., Krzascik, P., Headley, P. M., and Chizh, B. (1997). Novel antagonists of the glycine site of the NMDA receptor. Electrophysiological, biochemical and behavioural characterisation. J. Pharmacol. Exp. Ther. 283, 1264–1275.
- 222 Kew, J. N. C., and Kemp, J. A. (2005). Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology 179, 4–29.
- 223 Nowak, L., Bregestovski, P., Ascher, P., Herbet, A., and Prochiantz, A. (1984). Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307, 462–465.
- 224 Mayer, M. L., Westbrook, G. L., and Guthrie, P. B. (1984). Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309, 261–263.
- 225 Mayer, M. L., and Westbrook, G. L. (1987). Permeation and block of N-methyl-d-aspartic acid receptor channels by divalent cations in mouse cultured neurons. J. Physiol. Lond. 394, 501–527.
- 226 Lodge, D., and Anis, N. A. (1984). Effects of ketamine and three other short acting anaesthetics on spinal reflexes and inhibitions in the cat. Br. J. Anaesth. 56, 1143–1151.
- 227 Davies, S. N., and Lodge, D. (1987). Evidence for involvement of N-methylaspartate receptors in “wind-up” of class 2 neurones in the dorsal horn of the rat. Brain Res. 424, 402–406.
- 228 Holzman, S. G. (1982). Phencyclidine-like discriminative properties of opioids in the squirrel monkey. Psychopharmacology 77, 295–300.
- 229 Shannon, H. E. (1983). Pharmacological evaluation of N-allylnormetazocine (SKF10,047) on the basis of its discriminative properties. J. Pharmacol. Exp. Ther. 255, 144–152.
- 230 Berry, S. C., Dawkins, S. L., and Lodge, D. (1984). Comparison of sigma and kappa opioids as excitatory amino acid antagonists. Br. J. Pharmacol. 83, 179–185.
- 231 Berry, S. C., Anis, N. A., and Lodge, D. (1984). The effect of the dioxalanes on amino acid induced excitation in the mammalian spinal cord. Brain Res. 307, 85–90.
- 232 Church, J., Lodge, D., and Berry, S. C. (1985). Differential effects of dextrorphan and levorphanol on the excitation of rat spinal neurones by amino acids. Eur. J. Pharmacol. 111, 185–190.
- 233 Wong, E. H. F., Kemp, J. A., Priestley, T., Knight, A. R., Woodruff, G. N., and Iversen, L. L. (1986). The anticonvulsant MK-801 is a potent N-methyl-d-aspartate antagonist. Proc. Nat. Acad. Sci. 83, 7104–7108.
- 234 Domino, E. F., Chodoff, P., and Corssen, G. (1965). Pharmacological effects of CI-581, a new dissociative anesthetic in man. Clin. Pharmacol. Ther. 6, 279–291.
- 235
Keats, A. S., and
Telford, J.
(1964).
Narcotic antagonists as analgesics: Clinical aspects.
Adv. Chem.
45,
170–176.
10.1021/ba-1964-0045.ch014 Google Scholar
- 236 Lasagna, L., and Pearson, J. W. (1965). Analgesic and psychotomimetic properties of dexoxadrol. Proc. Soc. Exp. Med. 118, 352–354.
- 237 Luby, E. D., Cohen, B. D., Rosenbaum, G., Gotlieb, J. S., and Kelley, R. (1959). Study of a new schizophrenomimetic drug—Sernyl. Arch. Neurol. Psychiatry 81, 363–369.
- 238 Parsons, C. G., Danysz, W., and Quack, G. (1999). Memantine is a clinically well tolerated N-methyl-d-aspartate (NMDA) receptor antagonist—A review of preclinical data. Neuropharmacology 38, 735–767.
- 239 Sacco, R. L., DeRosa, J. T., Haley, E. C., Jr., Levin, B., Ordronneau, P., Phillips, S. J., Rundek, T., Snipes, R. G., and Thompson, J. L. (2001). Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: A randomized controlled trial. JAMA 285, 1719–1728.
- 240 Albers, G. W., Goldstein, L. B., Hall, D., and Lesko, L. M. (2001). Aptiganel hydrochloride in acute ischemic stroke: A randomized controlled trial. JAMA 286, 2673–2682.
- 241 Monaghan, D. T., and Larson, H. (1997). NR1 and NR2 subunit contributions to N-methyl-d-aspartate receptor channel blocker pharmacology. J. Pharmacol. Exp. Ther. 280, 614–620.
- 242 Rock, D. M., and Macdonald, R. L. (1992). Spermine and related polyamines produce a voltage-dependent reduction of N-methyl-d-aspartate receptor single channel conductance. Mol. Pharmacol. 42, 157–164.
- 243 Benveniste, M., and Mayer, M. L. (1993). Multiple effects of spermine on N-methyl-d-aspartic acid receptor responses of rat cultured hippocampal neurones. J. Physiol. 464, 131–163.
- 244 Williams, K. (1996). Separating dual effects of zinc at recombinant N-methyl-d-aspartate receptors. Neurosci. Lett. 215, 9–12.
- 245 Carter, C., Rivy, J. P., and Scatton, B. (1989). Ifenprodil and SL-82.0715 are antagonists at the polyamine site of the N-methyl-d-aspartate (NMDA) receptor. Eur. J. Pharmacol. 164, 611–612.
- 246 Williams, K. (1993). Ifenprodil discriminates subtypes of the N-methyl-d-aspartate receptor: Polyamine-like and high-affinity antagonist actions. J. Pharmacol. Exp. Ther. 266, 231–236.
- 247 Williams, K. (1995). Pharmacological properties of recombinant N-methyl-d-aspartate (NMDA) receptors containing the epsilon 4 (NR2D) subunit. Neurosci. Lett. 184, 181–184.
- 248 Schoemaker, H., Allen, J., and Langer, S. Z. (1990). Binding of [3H]ifenprodil, a novel NMDA antagonist, to a polyamine-sensitive site in the rat cerebral cortex. Eur. J. Pharmacol. 176, 249–250.
- 249 Church, J., Fletcher, E. J., Baxter, K., and Macdonald, J. F. (1994). Blockade by ifenprodil of high voltage-activated Ca2+ channels in rat and mouse cultured hippocampal pyramidal neurons—Comparison with N-methyl-d-aspartate receptor antagonist actions. Br. J. Pharmacol. 113, 499–507.
- 250 Avenet, P., Léonardon, J., Besnard, F., Graham, D., Depoortere, H., and Scatton, B. (1997). Antagonist properties of eliprodil and other NMDA receptor antagonists at rat NR1A/NR2A and NR1A/NR2B receptors expressed in Xenopus oocytes. Neurosci. Lett. 223, 133–136.
- 251 Fischer, G., Mutel, V., Trube, G., Malherbe, P., Kew, J. N. C., Mohaesi, E., Heitz, M. P., and Kemp, J. A. (1997). Ro 25-6981, a highly potent and selective blocker of NMDA receptors containing the NR2B subunit. Characterization in vitro. J. Pharmacol. Exp. Ther. 283, 1285–1292.
- 252 Chenard, B. L., Bordner, J., Butler, T. W., Chambers, L. K., Collins, M. A., Decosta, D. L., Ducat, M. F., Dumont, M. L., Fox, C. B., Mena, E. E., Menniti, F. S., Nielsen, J., Pagnozzi, M. J., Richter, K. E. G., Ronau, R. T., Shalaby, I. A., Stemple, J. Z., and White, W. F. (1995). (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol—A potent new neuroprotectant which blocks N-methyl-d-aspartate responses. J. Med. Chem. 38, 3138–3145.
- 253 Claiborne, C. F., McCauley, J. A., Libby, B. E., Curtis, N. R., Diggle, H. J., Kulagowski, J. J., Freidinger, R. M., Bednar, R. A., Mosser, S. D., Gaul, S. L., Connolly, T. M., Condra, C. L., Bednar, B., Stump, G. L., Lynch, J. J., Macauley, A., Wafford, K. A., Koblan, K. S., and Liverton, N. J. (2003). Orally efficacious NR2B-selective NMDA receptor antagonists. Bioorg. Med. Chem. Lett. 7, 2777–2780.
- 254 McCauley, J. A., Theberge, C. R., Romano, J. J., Billings, S. B., Anderson, K. D., Claremon, D. A., Freidinger, R. M., Bednar, R. A., Mosser, S. D., Gaul, S. L., Connolly, T. M., Condra, C. L., Xia, M., Cunningham, M. E., Bednar, B., Stump, G. L., Lynch, J. J., MacCauley, A., Wafford, K. A., Koblan, K. S., and Liverton, N. J. (2004). NR2B-selective N-methyl-d-aspartate antagonists: synthesis and evaluation of 5-substituted benzimidazoles. J. Med. Chem. 47, 2089–2096.
- 255 Buttelmann, B., Alanine, A., Bourson, A., Gill, R., Heitz, M. P., Mutel, V., Pinard, E., Trube, G., and Wyler, R. (2003). 4-(3,4-Dihydro-1H-isoquinolin-2yl)-pyridines and 4-(3,4-dihydro-1H-isoquinolin-2yl)-quinolines as potent NR1/2B subtype selective NMDA receptor antagonists. Bioorg. Med. Chem. Lett. 13, 1759–1762.
- 256 Wang, C. X., and Shuaib, A. (2005). NMDA/NR2B selective antagonists in the treatment of ischemic brain injury. Curr. Drug Targets 4, 143–151.
- 257 Higgins, G. A., Ballard, T. M., Enderlin, M., Haman, M., and Kemp, J. A. (2005). Evidence for improved performance in cognitive tasks following selective NR2B NMDA receptor antagonist pre-treatment in the rat. Psychopharmacology 179, 85–98.
- 258 Massey, P. V., Johnson, B. E., Moult, P. R., Auberson, Y. P., Brown, M. W., Molnar, E., Collingridge, G. L., and Bashir, Z. I. (2004). Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J. Neurosci. 24, 7821–7828.
- 259 Berberich, S., Punnakal, P., Jensen, V., Pawlak, V., Seeburg, P. H., Hvalby, O., and Kohr, G. (2005). 2B plasticity. J. Neurosci. 25, 6907–6910.
- 260 Brickley, S. G., Misra, C., Mok, M. H., Mishina, M., and Cull-Candy, S. G. (2003). NR2B and NR2D subunits coassemble in cerebellar Golgi cells to form a distinct NMDA receptor subtype restricted to extrasynaptic sites. J. Neurosci. 23, 4958–4966.
- 261 Lozovaya, N. A., Grebenyuk, S. E., Tsintsadze, T. Sh., Feng, B., Monaghan, D. T., and Krishtal, O. A. (2004). Extrasynaptic NR2B and NR2D subunits of NMDA receptors shape “superslow” afterburst EPSC in rat hippocampus. J. Physiol. 558, 451–463.
- 262 Hardingham, G. E., Fukunaga, Y., and Bading, H. (2002). Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405–414.
- 263 Ito, I., Tanabe, S., Kohda, A., and Sugiyama, H. (1990). Allosteric potentiation of quisqualate receptors by a nootropic drug aniracetam. J. Physiol. 424, 533–543.
- 264 Staubli, U., Perez, Y., Xu, F. B., Rogers, G., Ingvar, M., Stone-Elander, S., and Lynch, G. (1994). Centrally active modulators of glutamate receptors facilitate the induction of LTP in vivo. Proc. Nat. Acad. Sci. 91, 11158–11162.
- 265 Staubli, U., Rogers, G., and Lynch, G. (1994). Facilitation of glutamate receptors enhances memory. Proc. Nat. Acad. Sci. 91, 777–781.
- 266 Arai, A., and Lynch, G. (1998). The waveform of synaptic transmission at hippocampal synapses is not determined by AMPA receptor desensitization. Brain Res. 799, 230–234.
- 267 Arai, A., and Lynch, G. (1998). AMPA receptor desensitization modulates synaptic responses induced by repetitive afferent stimulation in hippocampal slices. Brain Res. 799, 235–242.
- 268 Arai, A. C., Kessler, M., Rogers, G., and Lynch, G. (2000). Effects of the potent Ampakine CX614 on hippocampal and recombinant AMPA receptors: Interactions with cyclothiazide and GYKI 52466. Mol. Pharmacol. 58, 802–813.
- 269 Danysz, W. (2002). CX-516 cortex pharmaceuticals. Curr. Opin. Investig. Drugs 3, 1081–1088.
- 270 Lynch, G. (2004). AMPA receptor modulators as cognitive enhancers. Curr. Opin. Pharmacol. 4, 4–11.
- 271 Yamada, K. A., and Rothman, S. M. (1992). Diazoxide blocks glutamate desensitization and prolongs excitatory postsynaptic currents in rat hippocampal neurons. J. Physiol. 458, 409–423.
- 272 Yamada, K. A., and Tang, C. M. (1993). Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents. J. Neurosci. 13, 3904–3915.
- 273 Bertolino, M., Baraldi, M., Parenti, C., Braghiroli, D., DiBella, M., Vicini, S., and Costa, E. (1993). Modulation of AMPA/kainate receptors by analogues of diazoxide and cyclothiazide in thin slices of rat hippocampus. Receptor Channels 1, 267–278.
- 274 Sekiguchi, M., Fleck, M. W., Mayer, M. L., Takeo, J., Chiba, Y., Yamashita, S., and Wada, K. (1997). A novel allosteric potentiator of AMPA receptors: 4-[2-(Phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide. J. Neurosci. 17, 5760–5771.
- 275 Miu, P., Jarvie, K. R., Radhakrishnan, V., Gates, M. R., Ogden, A., Ornstein, P. L., Zarrinmayeh, H., Ho, K., Peters, D., Grabell, J., Gupta, A., Zimmerman, D. M., and Bleakman, D. (2001). Novel AMPA receptor potentiators LY392098 and LY404187: Effects on recombinant human AMPA receptors in vitro. Neuropharmacology 40, 976–983.
- 276 Zarrinmayeh, H., Bleakman, D., Gates, M. R., Yu, H., Zimmerman, D. M., Ornstein, P. L., McKennon, T., Arnold, M. B., Wheeler, W. J., and Skolnick, P. (2001). [3H]N-2-(4-(N-benzamido)phenyl)propyl-2-propanesulfonamide: A novel AMPA receptor potentiator and radioligand. J. Med. Chem. 44, 302–304.
- 277 Quirk, J. C., and Nisenbaum, E. S. (2002). LY404187: a novel positive allosteric modulator of AMPA receptors. CNS Drug Rev. 8, 255–282.
- 278 Murray, T. K., Whalley, K., Robinson, C. S., Ward, M. A., Hicks, C. A., Lodge, D., Vandergriff, J. L., Baumbarger, P., Siuda, E., Gates, M., Ogden, A. M., Skolnick, P., Zimmerman, D. M., Nisenbaum, E. S., Bleakman, D., and O'Neill, M. J. (2003). LY503430, a novel α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor potentiator with functional, neuroprotective and neurotrophic effects in rodent models of Parkinson's disease. J. Pharmacol. Exp. Ther. 306, 752–762.
- 279 O'Neill, M. J., Bleakman, D., Zimmerman, D. M., and Nisenbaum, E. S. (2004). AMPA receptor potentiators for the treatment of CNS disorders. Curr. Drug Targets 3, 181–194.
- 280 Baumbarger, P., Muhlhauser, M., Zhai, J., Yang, C. R., and Nisenbaum, E. S. (2001). Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in prefrontal cortical pyramidal neurons by a novel allosteric potentiator. J. Pharmacol. Exp. Ther. 298, 86–102.
- 281 Vandergriff, J., Huff, K., Bond, A., and Lodge, D. (2001). Potentiation of responses to AMPA on central neurons by LY392098 and LY404187 in vivo. Neuropharmacology 40, 1003–1009.
- 282 Quirk, J. C., and Nisenbaum, E. S. (2003). Multiple molecular determinants for allosteric modulation of alternatively spliced AMPA receptors. J. Neurosci. 23, 10953–10962.
- 283 Partin, K. M., Fleck, M. W., and Mayer, M. L. (1996). AMPA receptor flip/flop mutants affecting deactivation, desensitization, and modulation by cyclothiazide, aniracetam, and thiocyanate. J. Neurosci. 16, 6634–6647.
- 284 Jin, R., Clark, S., Weeks, A. M., Dudman, J. T., Gouaux, E., and Partin, K. M. (2005). Mechanism of positive allosteric modulators acting on AMPA receptors. J. Neurosci. 25, 9027–9036.
- 285 Dimond, S. J., Scammell, R. E., Pryce, I. G., Huws, D., and Gray, C. (1979). Some effects of piracetam (UCB 6215 Nootropyl) on chronic schizophrenia. Psychopharmacology 64, 341–348.
- 286 Lee, C. R., and Benfield, P. (1994). Aniracetam. An overview of its pharmacodynamic and pharmacokinetic properties, and a review of its therapeutic potential in senile. Drugs and Aging 4, 257–273.
- 287 Oepen, G., Eisele, K., Thoden, U., and Birg, W. (1985). Piracetam improves visuomotor and cognitive deficits in early Parkinsonism—A pilot study. Pharmacopsychiatry 18, 343–346.
- 288
Granger, R.,
Deadwyler, S.,
Davis, M.,
Moskovitz, B.,
Kessler, M.,
Rogers, G., and
Lynch, G.
(1996).
Facilitation of glutamate receptors reverses an age-associated memory impairment in rats.
Synapse
22,
332–337.
10.1002/(SICI)1098-2396(199604)22:4<332::AID-SYN4>3.0.CO;2-C CAS PubMed Web of Science® Google Scholar
- 289 Hampson, R. E., Rogers, G., Lynch, G., and Deadwyler, S. A. (1998). Facilitative effects of the ampakine CX516 on short-term memory in rats: Enhancement of delayed-nonmatch-to-sample performance. J. Neurosci. 18, 2740–2747.
- 290 Pontecorvo, M. J., and Evans, H. L. (1985). Effects of aniracetam on delayed matching-to-sample performance of monkeys and pigeons. Pharmacol. Biochem. Behav. 22, 745–752.
- 291 Verloes, R., Scotto, A. M., Gobert, J., and Wulfert, E. (1988). Effects of nootropic drugs in a scopolamine-induced amnesia model in mice. Psychopharmacology 95, 226–230.
- 292 Bhattacharya, S. K., Sen, A. P., Upadhyay, S. N., and Jaiswal, A. K. (1993). Anxiolytic activity of piracetam, a nootropic agent, following subchronic administration in rodents. Ind. J. Exp. Biol. 31, 902–907.
- 293 File, S. E., Hyde, J. R., and Odling-Smee, F. J. (1979). Piracetam impairs the overshadowing of background stimuli by an informative CS. Physiol. Behav. 23, 827–830.
- 294 Gainetdinov, R. R., Mohn, A. R., Bohn, L. M., and Caron, M. G. (2001). Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter. Proc. Nat. Acad. Sci. USA 98, 11047–11054.
- 295 Johnson, S. A., Luu, N. T., Herbst, T. A., Knapp, R., Lutz, D., Arai, A., Rogers, G. A., and Lynch, G. (1999). Synergistic interactions between ampakines and antipsychotic drugs. J. Pharmacol. Exp. Ther. 289, 392–397.
- 296 Hayashi, T., Umemori, H., Mishina, M., and Yamamoto, T. (1999). The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn. Nature 397, 72–76.
- 297 Legutko, B., Li, X., and Skolnick, P. (2001). Regulation of BDNF expression in primary neuron culture by LY392098, a novel AMPA receptor potentiator. Neuropharmacology 40, 1019–1027.
- 298 Lauterborn, J. C., Lynch, G., Vanderklish, P., Arai, A., and Gall, C. M. (2000). Positive modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons. J. Neurosci. 20, 8–21.
- 299 Duman, R. S. (2004). Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromol. Med. 5, 11–25.
- 300 Nibuya, M., Morinobu, S., and Duman, R. S. (1995). Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J. Neurosci. 15, 7539–7547.
- 301 Russo-Neustadt, A., Ha, T., Ramirez, R., and Kesslak, J. P. (2001). Physical activity-antidepressant treatment combination: Impact on brain-derived neurotrophic factor and behavior in an animal model. Behav. Brain Res. 120, 87–95.
- 302 Skolnick, P. (1999). Antidepressants for the new millennium. Eur. J. Pharmacol. 30, 31–40.
- 303 Li, X., Tizzano, J. P., Griffey, K., Clay, M., Lindstrom, T., and Skolnick, P. (2001). Antidepressant-like actions of an AMPA receptor potentiator (LY392098). Neuropharmacology 40, 1028–1033.
- 304 O'Neill, M. J., Murray, T. K., Clay, M. P., Lindstrom, T., Yang, C. R., and Nisenbaum, E. S. (2005). LY503430: Pharmacology, pharmacokinetics, and effects in rodent models of Parkinson's disease. CNS Drug Rev. 11, 77–96.
- 305 Tarnawa, I., Bersenyi, P., Andrasi, F., Botka, P., Hamori, T., Ling, I., and Korosi, J. (1993). Structure–activity relationships of 2,3-benzodiazepine compounds with glutamate antagonistic action. Bioorg. Med. Chem. Lett. 3, 99–104.
- 306 Ruel, J., Guitton, M. J., and Puel, J. L. (2002). Negative allosteric modulation of AMPA-preferring receptors by the selective isomer GYKI 53784 (LY303070), a specific non-competitive AMPA antagonist. CNS Drug Rev. 8, 235–254.
- 307 Donevan, S. D., Yamaguchi, S., and Rogawski, M. A. (1994). Non-N-methyl-d-aspartate receptor antagonism by 3-N-substituted 2,3-benzodiazepines: Relationship to anticonvulsant activity. J. Pharmacol. Exp. Ther. 271, 25–29.
- 308 Paternain, A. V., Morales, M., and Lerma, J. (1995). Selective antagonism of AMPA receptors unmasks kainate receptor-mediated responses in hippocampal neurons. Neuron 14, 185–189.
- 309 Bleakman, D., Ballyk, B. A., Schoepp, D. D., Palmer, A. J., Bath, C. P., Sharpe, E. F., Wooley, M. L., Bufton, H. W., Kamboj, R. K., Tarnawa, I., and Lodge, D. (1996). Activity of 2,3-benzodiazepines at native rat and recombinant human glutamate receptors in vitro: Stereospecificity and selectivity profiles. Neuropharmacology 35, 1689–1702.
- 310 Rammes, G., Swandulla, D., Collingridge, G. L., Hartmann, S., and Parsons, C. G. (1996). Interactions of 2,3 benzodiazepines and cyclothiazide at AMPA receptors: Patch clamp recordings in cultured neurons and area CA1 in hippocampal slices. Br. J.Pharmacol. 117, 1209–1221.
- 311 Chenard, B. L., Menniti, F. S., Pagnozzi, M. J., Shenk, K. D., Ewing, F. E., and Welch, W. M. (2000). Methaqualone derivatives are potent noncompetitive AMPA receptor antagonists. Bioorg. Med. Chem. Lett. 10, 1203–1205.
- 312 Menniti, F. S., Chenard, B. L., Collins, M. B., Ducat, M. F., Elliott, M. L., Ewing, F. E., Huang, J. I., Kelly, K. A., Lazzaro, J. T., Pagnozzi, M. J., Weeks, J. L., Welch, W. M., and White, W. F. (2000). Characterisation of the binding site for a novel class of noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonists. Mol. Pharmacol. 58, 1310–1317.
- 313 Welch, W. M., Ewing, F. E., Huang, J., Menniti, F. S., Pagnozzi, M. J., Kelly, K., Seymour, P. A., Guanowsky, V., Guhan, S., Guinn, M. R., Critchett, D., Lazzaro, J., Ganong, A. H., DeVries, K. M., Staigers, T. L., and Chenard, B. L. (2001). Atropisomeric quinazolin-4-one derivatives are potent noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. Bioorg. Med. Chem. Lett. 11, 177–181.
- 314 Lazzaro, J. T., Paternain, A. V., Lerma, J., Chenard, B. L., Ewing, F. E., Huang, J., Welch, W. M., Ganong, A. H., and Menniti, F. S. (2002). Functional characterisation of CP-465,022, a selective, noncompetitive AMPA receptor antagonist. Neuropharmacology 42, 143–153.
- 315 Partin, K. M., and Mayer, M. L. (1996). Negative allosteric modulation of wild-type and mutant AMPA receptors by GYKI 53655. Mol. Pharmacol. 49, 142–148.
- 316 Solyom, S., and Tarnawa, I. (2002). Non-competitive AMPA antagonists of 2,3-benzodiazepine type. Curr. Pharm. Des. 8, 913–939.
- 317 Czuczwar, S. J., Swiader, M., Kuzniar, H., Gasior, M., and Kleinrok, Z. (1998). LY 300164, a novel antagonist of AMPA/kainate receptors, potentiates the anticonvulsive activity of antiepileptic drugs. Eur. J. Pharmacol. 23, 103–109.
- 318 Filliat, P., Pernot-Marino, I., Baubichon, D., and Lallement, G. (1998). Behavioral effects of NBQX, a competitive antagonist of the AMPA receptors. Pharmacol. Biochem. Behav. 59, 1087–1092.
- 319 Kapus, G., Szekely, J. I., Durand, J., Ruiz, A., and Tarnawa, I. (2000). AMPA receptor antagonists, GYKI 52466 and NBQX, do not block the induction of long-term potentiation at therapeutically relevant concentrations. Brain Res. Bull. 52, 511–517.
- 320 Chappell, A. S., Sander, J. W., Brodie, M. J., Chadwick, D., Lledo, A., Zhang, D., Bjerke, J., Kiesler, G. M., and Arroyo, S. (2002). A crossover, add-on trial of talampanel in patients with refractory partial seizures. Neurology 58, 1680–1682.
- 321 Everts, I., Petroski, R., Kizelsztein, P., Teichberg, V. I., Henemann, S. F., and Hollman, M. (1999). Lectin-induced inhibition of desensitization of the kainate receptor GluR6 depends on the activation state and can be mediated by a single native ectopic N-linked carbohydrate side chain. J. Neurosci. 19, 916–927.
- 322 Paternain, A. V., Rodríguez-Moreno, A., Villarroel, A., and Lerma, J. (1998). Activation and desensitization properties of native and recombinant kainate receptors. Neuropharmacology 37, 1249–1259.
- 323 Jones, K. A., Wilding, T. J., Huettner, J. E., and Costa, A. M. (1997). Desensitization of kainate receptors by kainate, glutamate and diastereomers of 4-methylglutamate. Neuropharmacology 36, 853–863.
- 324 Huettner, J. E. (1990). Glutamate receptor channels in rat DRG neurons: Activation by kainate and quiqualate and blockade of desensitization by Con A. Neuron 5, 255–266.
- 325 Valgeirsson, J., Nielsen, E. Ø., Peters, D., Varming, T., Mathiesen, C., Kristensen, A. S., and Madsen, U. (2003). 2-Arylureidobenzoic acids: Selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5. J. Med. Chem. 46, 4383–4386.
- 326 Valgeirsson, J., Nielsen, E. Ø., Peters, D., Mathiesen, C., Kristensen, A. S., and Madsen, U. (2004). Bioisosteric modifications of 2-arylureidobenzoic acids: Selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5. J. Med. Chem. 47, 6948–6957.
