AMPA antagonists

Figure 10.4 Structures of some antagonists at the various receptors for glutamate. CNQX is an AMPA antagonist but NQQX has greater selectivity. AP-5 is an NMDA receptor antagonist while MK-801 blocks the NMDA receptor channel (non-competitive)...

Further new competitive AMPA antagonists include the imidazo-fused 23-benzodiazepine derivative 103. This compound showed excellent anticonvulsant activity and other activities indicative of possible therapeutic significance in human stroke and Parkinson k disease <00BMC2127>. An efficient synthesis of fluorine-containing H-1,4-diazepino[6,5-/t]quinolines has been described based on iV,/V-dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine and an aromatic nucleophilic displacement with 1,2-ethylenediamine, followed by cyclocondensation <00S1822>. 

Guisbert, A.L. et al.. Enantiomeric separation of an AMPA antagonist using a CHIROBIOTIC T colunm with HPLC and evaporative light-scattering detection, J. Liq. Chrom. Rel. Technol., 23, 1019, 2000. 

Ruel J., Guitton M. J., and Puell 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. 

Fig. 10.1 Chemical structures of NMDA and AMPA antagonists used for the treatment of ischemic injury in animal models. PCP (a) MK-801 (b) Dextrorphan (c) and Dextromethorphan (d)...

YM872 is an AMPA antagonist that reduced infarct volume in animal models (Shimizu-Sasamata et al., 1996 Kawasaki-Yatsugi et al., 2000). Two clinical trials of YM872 were terminated prematurely. The first trial, ARTIST (AMPA Receptor... 

The Pharmacology of AMPA Antagonists and Their Role in Neuroprotection... 

Ossowska K, Pietraszek M, Wardas J, Wolfarth S. 2004. Potential antipsychotic and extrapyramidal effects of (R,S)-3,4-dicarboxyphenylglycine [(R,S)-3,4-DCPG], a mixed AMPA antagonist/mGluR8 agonist. Pol j pharmacol 56 ... 

FIGURE 16.24 The heptacyclic AMPA antagonist GYKI 53 655 and ring-contracted analogs. ... 

LY300164 (GYKI 53655) was a more potent AMPA antagonist than GYKI 52466 on spinal neurones but had the same selectivity [96]. For example, following intravenous (5mg/kg) or oral (lOmg/kg) administration, LY300164 reduces AMPA responses by 80-100% with only minor effects on responses to NMDA. 

The interaction between AP and AMPA receptors is complex and may vary with cell type and the specific form of the AP peptide. For instance Api-42 toxicity is attenuated in retinal neurons following blockade of AMPA receptors [130], while AP25-35 toxicity in cerebellar granule cells is enhanced by AMPA antagonists [131]. While the reasons for these mechanistic differences are not entirely clear, the effects of AP on AMPA function may be mediated indirectly via increases in extracellular glutamate, rather than a direct modulatory effect of the peptide on the AMPA receptor itself. Additional support for a role of AMPA receptors in AD... 

Gill R, Lodge D (1997) Pharmacology of AMPA antagonists and their role in neuroprotection. Int Rev Neurobiol 40 197-232... 

Zadow B, Schmidt WJ (1994) The AMPA antagonists NBQX and GYKI 52466 do not counteract neuroleptic-induced catalepsy. Naunyn Schmiedebergs Arch Pharmacol 349 61-65... 

Loschmann PA, Lange KW, Kunow M et al (1991) Synergism of the AMPA-antagonist NBQX and the NMDA-antagonist CPP with L-dopa in models of Parkinson s disease. J Neural Transm Park Dis Dement Sect 3 203-213... 

Turski, L., Huth, A., Sheardown, M., McDonald, F., Neuhaus, R., Schneider, H., Dirnagl, U., Wiegand, F., Jacobsen, P., Ottow, E., 1998. ZK20075 a phosphonate quinoxalinedione/(AMPA) antagonist for neuroprotection in stroke and trauma. Proc. Natl. Acad. Sci. 

Excitotoxicity also plays a role in epileptic seizures and cerebral ischemia. During ischemic injury, a rapid accumulation of glutamate takes place. This induces a noxious Ca + influx into the cytoplasm. The Ca + conductance of NMDA receptors explains the efficacy of NMDA antagonists against hypoxic damage. In addition, AMPA antagonists have also a protective function in hypoxia (Siesjo et al., 1991)... 

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