AMPA Receptor Antagonists

Abstract

AMPA Receptor antagonists have received considerable attention in recent years. Within the class of excitatory amino acid receptor antagonists AMPA receptor antagonists have shown excellent neuroprotection in several models of cerebral ischemia and neuronal injury. However, poor physical properties have been a major limiting factor in developing these as viable drug candidates. The quinoxaline-2,3-dione template has been the backbone of various competitive AMPA receptor antagonists such as NBQX, PNQX, YM-90K and more recently ZK200775. The SAR learned from these have been valuable for developing the AMPA pharmacophore model (Fig. 2) and has been discussed in detail in this review. There have been efforts in this area to design very selective AMPA receptor antagonists by minimizing the interaction at the NMDA associated GlyN receptors. Compounds designed by BASF and Yamanouchi have been successful in these efforts and their compounds show excellent affinity for the AMPA receptors. Efforts by Warner-Lambert and Novartis also highlight significant success in developing balanced AMPA and GlyN receptor antagonists. Non-competitive AMPA receptor antagonists are also being pursued for various neurological disorders including neuroprotection and are divided in two major classes, viz. positive and negative allosteric modulators. The physical properties of negative allosteric modulators such as GYKI 52466, which belong to the 2,3-benzodiazepinyl structural class have been significantly better. However, the in vitro activity of these compounds has been in the micromolar range and the overall class has the disadvantage of not having a high throughput assay. Other classes of compounds such as phthalazines and quinazolines are being developed and have raised hopes for the second generation of compounds in this area.

Glutamate Dysfunction in Hippocampus: Relevance of Dentate Gyrus and CA3 Signaling

“…[1][2][3] The glutamate system in brain is highly complex and includes multiple interacting receptors, modulating cotransmitters and multisystem synapses (figure 1). Presynaptic, postsynaptic, and astrocytic mechanisms are important to overall excitatory signaling and to unique plasticity mechanisms which are associated with glutamate transmission [4][5][6] ; the 3 compartments (pre-, postsynaptic, and astrocytic) are all candidate systems for pathology in glutamate-related brain diseases.…”

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

“…These structural requirements are in accordance with those emphasized in the pharmacophore models of the AMPA receptor reported in the literature for the binding of quinoxalinedione and heterocyclic-fused quinoxalinone antagonists. 10,[16][17][18]36) Among the previously reported TQX series, the 7-chloro-4,5-dihydro-4-oxo-8-(1,2,4-triazol-4-yl)-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylic acid TQX-173 and its corresponding ethyl ester (Fig. 1), both bearing a (1,2,4-triazol-4-yl) moiety at the crucial 8-position, emerged as two of the most active and selective TQX compounds toward the AMPA receptor.…”

“…27,29) Thus, it can be hypothesized that the 8-heteroaryl group on the TQX framework interacts with a hydrophobic receptor region which also contains a hydrogen bond donor site. 10,[16][17][18]36) Pursuing our studies on the SAR of the TQX series, the 8- Universita' degli Studi di Firenze; Viale G. Pieraccini, 6, 50134 Firenze, Italy. Received December 19, 2007; accepted April 30, 2008; published online May 8, 2008 In this paper, we report a study on some new 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylate derivatives (TQXs), bearing a nitrogen-containing heterocycle at position-9, and designed as (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonists.…”

Mild and efficient synthesis of new tetraketones as lipoxygenase inhibitors and antioxidants

“…In mammalian cells these are key enzymes in the biosynthesis of a variety of bioregulatory compounds such as hydroxyeicosatetraenoic acids (HETEs), leukotrienes, lipoxins and hepoxylines [4]. It has been found that these lipoxygenase products play a role in a variety of disorders such as inflammation [5], tumor angiogenesis [6] and bronchial asthma [7]. LOXs are therefore a potential target for the rational drug design and discovery of mechanismbased inhibitors for the treatment of inflammation, bronchial asthma, cancer and autoimmune diseases.…”