Competitive AMPA receptor antagonists

Abstract

Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) where it is involved in the physiological regulation of different processes. It has been well established that excessive endogenous Glu is associated with many acute and chronic neurodegenerative disorders such as cerebral ischaemia, epilepsy, amiotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease. These data have consequently added great impetus to the research in this field. In fact, many Glu receptor antagonists acting at the N-methyl-D-aspartic acid (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), and/or kainic acid (KA) receptors have been developed as research tools and potential therapeutic agents. Ligands showing competitive antagonistic action at the AMPA type of Glu receptors were first reported in 1988, and the systemically active 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline (NBQX) was first shown to have useful therapeutic effects in animal models of neurological disease in 1990. Since then, the quinoxaline template has represented the backbone of various competitive AMPA receptor antagonists belonging to different classes which had been developed in order to increase potency, selectivity and water solubility, but also to prolong the "in vivo" action. Compounds that present better pharmacokinetic properties and less serious adverse effects with respect to the others previously developed are undergoing clinical evaluation. In the near future, the most important clinical application for the AMPA receptor antagonists will probably be as neuroprotectant in neurodegenerative diseases, such as epilepsy, for the treatment of patients not responding to current therapies. The present review reports the history of competitive AMPA receptor antagonists from 1988 up to today, providing a systematic coverage of both the open and patent literature.

Acute nicotine changes dynorphin and prodynorphin mRNA in the striatum

“…Neither systemic nor intrategmental or intra-accumbal administration of AMPA antagonists (CNQX, GYKI-52466, NBQX) blocks the nicotine-induced dopamine overflow in nucleus accumbens in vivo (Sziraki et al 1998(Sziraki et al , 2002Schilström et al 1998;Fu et al 2000;Kosowski et al 2002 and discussion therein), and blockade of AMPA receptors with DNQX inhibits about 20% of the dopamine release elicited by a high concentration of nicotine in striatal slices (Wonnacott et al 2000). Because the quinoxalinedione-derived AMPA antagonists DNQX and NBQX also possess affinity for the Gly/NMDA site (Catarzi et al 2007), it is possible that the observed effect on dopamine release in striatal slices and Dyn content in our studies is mediated via NMDA receptors. Based on the literature, we surmise that the excitatory amino acid could influence Dyn synthesis in the striatum indirectly by modulating nicotine-stimulated dopamine release and subsequent dopamine-mediated opioid peptide synthesis.…”

Inhibition of Calcineurin-mediated Endocytosis and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Prevents Amyloid β Oligomer-induced Synaptic Disruption

“…It remains to be determined why interaction with this binding site has the stronger effect on ADDL binding to neurons. The GYKI class AMPAR antagonists are neuroprotective in a variety of animal disease models (70,71,73,74). As increased epileptiform activities develop in transgenic mice, presumably because of accumulated A␤ levels in the brain (75), it will be important to determine whether GYKI25466 can protect AD transgenic mice through its inhibitory effect of ADDL binding-AMPAR interaction, which if true would offer a potential approach for treating the neuronal dysfunction and cognitive deficits in AD.…”

Synthesis and Biological Evaluation of Novel 9-Heteroaryl Substituted 7-Chloro-4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates (TQX) as (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid (AMPA) Receptor Antagonists

“…[5][6][7][8][9][10][11][12] An approach to antagonize the overstimulation of postsynaptic iGluRs by excessive endogenous Glu is represented by the use of AMPA receptor antagonists that, together with other Glu receptor antagonists, have been proposed as potential useful neuroprotectives for the prevention and treatment of the above mentioned neurological disorders. [10][11][12][13][14][15][16][17][18][19][20] The success of AMPA receptor antagonists as potential therapeutic agents is in part due to their greater clinical potential with respect to other pharmacologically well-characterized iGluR antagonists: for example, AMPA receptor antagonists do not produce the adverse psychotomimetic and cardiovascular effects observed for competitive NMDA receptor antagonists.21) These data have consequently added great impetus for the development of AMPA receptor antagonists as research tools.In the course of our efforts to find novel competitive AMPA receptor antagonists, [22][23][24][25][26][27][28][29][30][31][32][33][34][35] we have published works which report the synthesis and pharmacological studies on 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates (TQXs) bearing different substituents on the fused benzo moiety (Series A, Fig. 1).…”