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.