Pharmacology of Excitatory Amino Acids

Collingridge, G.L. and Singer, W. (1991) Excitatory amino acid receptors and synaptic plasticity. In D. Lodge and G.L. Collingridge (Eds.), Trends in Pharmacological Science, The Pharmacology of Excitatory Amino acids. Special Report, Elsevier, Amsterdam, pp. 24-48. 

Okano, K., Kuraishi, Y., Satoh, M. Pharmacological evidence for involvement of excitatory amino acids in aversive responses induced by intrathecal substance P in rats, Biol. Pharm. Bull. 

Riluzol antagonizes glutamatergic transmission via different mechanisms indirect blockade of NMDA receptors (modification of receptor phosphorylation status), inhibition of excitatory amino acid release by an agonist effect on an unknown receptor bound to protein G or interaction with voltage-dependent sodium channels (depressor effect on neurones with a high tonic activity spontaneously). The pharmacological properties of the compound can be explained by these mechanisms anti-seizure, anti-ischaemia, antagonism of MPTP cytotoxicity [201]. 

Compounds that have agonistic properties at glutamate or aspartate receptors are also CNS stimulants, readily cause convulsions, and presumably could also be employed as analeptics. Three separate excitatory amino acid receptor subtypes have been characterized pharmacologically, based on the relative potency of synthetic agonists. These three receptors are named for their respective prototypical agonists A/-methyl-D-aspartate [6384-92-5]... 

Monaghan, D. T., Bridges, R. J. Cotman, C. W. (1989). The excitatory amino acid receptors their classes, pharmacology and distinct properties in the function of the central nervous system. A Rev. Pharmacol Toxicol. 29, 365-402. 

Faure, S., Jensen, A.A., Maurat, V., Gu, X., Sagot, E., Aitken, D.J., Bolte, J., Gefflaut, T. and Bunch, L., Stereoselective chemoenzymatic s3mthesis of the four stereoisomers of l-2-(2-carboxycyclobutyl)glycine and pharmacological characterization at human excitatory amino acid transporter subtypes 1, 2, and 3. J. Med. Chem., 2006, 49, 6532-6538. 

Anatomical and pharmacological studies have both indicated that the two major transmitter systems within the brain are the inhibitory GABA ergic and the excitatory amino acid (EAA) pathways [264]. At least four different receptors mediate the action of EAA, they are named according to the most selective li-... 

Pharmacology Persistent activation of CNS N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer disease. Memantine is an NMDA receptor antagonist. 

Derrick BE, Martinez Jr JL (1996) Associative, bidirectional modifications at the hippocampal mossy fibre-CA3 synapse. Nature 381 429-434 Dickenson A (1997) Mechanisms of central hypersensitivity excitatory amino acid mechanisms and their control. In Dickenson A, Besson JM (eds) Pharmacology of pain. Springer-Verlag, Berlin, pp 167-210... 

Schmidt WJ, Kretschmer BD (1997) Behavioural pharmacology of glutamate receptors in the basal ganglia. Neurosci Biobehav Rev 21 381-392 Schmidt WJ, Bubser M, Hauber W (1990) Excitatory amino acids and Parkinson s disease. Trends Neurosci 13 46... 

Glutamate is the major excitatory amino acid in the brain. It has a key role in learning and memory and is involved in the mediation of the response to stress. Glutamate receptors are present throughout the central nervous system but differ widely according to their localisation and function (Kent et al. 2002), and as a result have not been easy to identify as targets for pharmacological manipulation. 

Schoepp D., Bockaert J., and Sladeczek F. (1990). Pharmacological and functional characteristics of metabotropic excitatory amino acid receptors. Trends Pharmacol. Sci. 11 508-515. 

Dunlop J., Lou Z., Zhang Y., and Mcllvain H. B. (1999). Inducible expression and pharmacology of the human excitatory amino acid transporter 2 subtype of L-glutamate transporter. Br. J. Pharmacol. 128 1485-1490. 

Both phencyclidine and ketamine bind with high affinity to a number of receptors in the brain, but it is now accepted that the primary target is the sigma-PCP receptor site located in the ion channel of the NMDA excitatory amino acid receptor complex. The precise function of this receptor in the brain is still the subject of debate. It is now known that there are two distinct sigma receptor sites in the mammalian brain (ctj and a2) which are not associated with the NMDA receptor complex. Haloperidol and the atypical neuroleptic remoxipride bind with high affinity to such sites, and it has been postulated that some typical and atypical neuroleptics may owe some of their pharmacological effects to their action on such receptors. 

Long, J. B., Rigamonti, D. D., Oleshansky, M. A., Wingfield, C. P., and Martinez-Arizala, A. (1994). Dynorphin A-induced rat spinal cord injury Evidence for excitatory amino acid involvement in a pharmacological model of ischemic spinal cord injury.. Pharmacol. Exp. Ther. 269, 358—366. Malan, T. P., Ossipov, M. H., Gardell, L. R., Ibrahim, M., Bian, D., Lai, J., and Porreca, E (2000). Extraterritorial neuropathic pain correlates with multisegmental elevation of spinal dynorphin in nerve-injured rats. Pain 86, 185—194. 

Here we investigate the neuroprotective potential of BEO in vivo by using an experimental model of focal brain ischemia in rats. Moreover, we evaluate whether neuroprotection is associated with altered levels of excitatory neurotransmitters and with a modulation of PI3-K/Akt pathway in the ischemic cortex. Our results indicate that BEO indeed protects against ischemic injury in an in vivo model of permanent focal brain ischemia in rat and that neuroprotection is associated with reduced excitatory amino acid efflux induced by MCAo in the ischemic cortex and elevation ofp-Akt and phospho-GSK-3/3 (p-GSK-3/3) levels in the ischemic penumbra. A preliminary account of this in vivo study has been communicated to the British Pharmacologic Society (Morrone et al., 2006). 

Yamamoto T, Yaksh TL (1992) Spinal pharmacology of thermal hyperesthesia induced by constriction injury of sciatic nerve. Excitatory amino acid antagonists. Pain 49 121-128 Yamamoto Y, Ono H, Ueda A, Shimamura M, Nishimura K, Hazato T (2002b) Spinorphin as an endogenous inhibitor of enkephahn-degrading enzymes roles in pain and inflammation. Curr Protein Pept Sci 3 587-599... 

Brauner-Osborne, H., Nielson, B., Stensbol, T.B., Johanson, TN. and Skjaerbaek, N. (1997) Molecular pharmacology of 4-substituted glutamic acid analogues at ionotropic and metatropic excitatory amino acid receptors. Eur.. Pharmacol., 335, Rl-3. 

Krogsgaard-Larsen, P, Ferkany, J. W., Nielsen, E. O., Madsen, U., Ebert, B., Johansen, J. S., Diemer, S. H., Bruhn, T, Beattie, D. T, Curtis, D. R. Novel class of amino acid antagonists at non-N-methyl-D-aspartic acid excitatory amino acid receptors. Synthesis, in vitro and in vivo pharmacology, and neuroprotection. J. Med. Chem. 1991,54,123-130. 

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