Chapter 5. Recent Advances in Excitatory Amino Acid Research

Abstract

This chapter discusses the recent advances across the spectrum of excitatory amino acid (EAA) research. The chapter also discusses the structure and mechanism of action of new EAA based therapeutic agents. EAAs have been shown to mediate a range of physiological functions, including nociception, vision, cardiovascular reflex, respiration, and motor control. EAAs have been suggested to play a role in the etiology of epilepsy. Competitive and non-competitive N-methyl-D-aspartic acid (NMDA) antagonists also have been shown to exert a protective action in animal models of anxiety. A central role for EAAs in stroke has been firmly established. The second messenger pathways, associated with EAA receptor activation, have been discussed in this chapter. NMDA receptor activation has been shown to stimulate the arachidonic acid cascade and induced proteolysis of brain spectrin. The AP4 (or APB) receptor is the least well characterized of the EAA receptors. But the NMDA receptor is the best characterized among them. The nature of interaction of the NMDA and phencyclidine (PCP) receptors has been defined, further using both receptor binding and electrophysiology. Binding of PCP site ligands are reported to be dependent on both NMDA receptor activation and membrane potential. From the high level of pharmaceutical interest in NMDA antagonists, increasing numbers of new antagonist structures have appeared. However, no deviations from the amino acid-spacer-phosphonic acid structural type have been reported. Dextromethorphan and MK-801 have been patented as an antineurotoxic agent. In addition, other opioids and nonopioids, including naloxone, have also been reported to protect against neurotoxicity in vitro . The stoichiometry of the glycine modulation of the NMDA receptor has been determined. It is clear that the foundation now exists to support rapid future progress in the area of excitatory amino acid research.