Some chemical highlights in the development of excitatory amino acid pharmacology

Important findings in the excitatory amino acid (EAA) field that have stemmed directly from work initiated in chemical laboratories are discussed from a historical point of view, showing how each has contributed to our present knowledge of EAA receptors. The groups of compounds discussed include simple analogues and derivatives of short-chain excitatory amino acids, longer-chain analogues, analogues containing ring structures essential to the acidic nature of the omega-terminal, and conformationally restricted agonists and antagonists. Recent interest has centered on antagonists for the N-methyl-D-aspartate (NMDA) and alpha-methyl-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptors typified by the long-chain omega-phosphono amino acids and the quinoxalinediones, respectively. Consideration of conformational aspects of both agonists and antagonists is currently providing considerable insight into the disposition of charged sites and general topological features in the various receptors, as well as the likely conformation adopted by L-glutamate in its physiological interaction with these receptors.