Glutamate and aspartate appear to be the major excitatory neurotransmitters in the mammalian central nervous system (CNS). Even so, these transmitters are the most poorly understood ones in the brain, particularly at the level of their receptors. This proposal outlines a project designed to achieve a better understanding of the structural details of how amino acids bind to receptors. Specifically, the synthesis of three receptor models is proposed. These models have been designed to mimic receptor-substrate binding selectivities of the three known classes of glutamate receptors (quisquate, N-methyl-d-asparatate, and kainate), based on a hypothesis that receptor selectivities arise from easily understood conformational preferences in glutamate an its analogues that define the receptor classes. It is anticipated that conformational details of the binding of substrates to larger molecules will be obtained, and that the binding characteristics of the various glutamate receptor classes will be better understood at a molecular level.
| Bridges, R J; Stanley, M S; Anderson, M W et al. (1991) Conformationally defined neurotransmitter analogues. Selective inhibition of glutamate uptake by one pyrrolidine-2,4-dicarboxylate diastereomer. J Med Chem 34:717-25 |
