Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system, as well as a potent neurotoxin if not properly regulated. During nerve impulse transmission vesicles containing glutamate are released from the presynaptic neuron, and travel across the synaptic cleft, where they bind to and activate glutamate receptors (e.g., AMPA, NMDA and KA) on postsynaptic neurons. This results in depolarization of the postsynaptic neuron and generation of an action potential. The extracellular levels of the transmitter and consequently, access to receptors, is thought to be regulated by the sodium- dependent excitatory amino acid transporters (EAATs 1-5). While all of these receptors and transporters bind the endogenous transmitter L-glutamate, synthetic and naturally occurring analogues have been identified that differentiate the respective binding sites. More recently, a distinct transporter (System Xc-), that mediates the obligate exchange of L-glutamate and L-cystine, has been identified in the CNS and postulated to also influence the access of glutamate to receptors. The cross-reactivity of ligands previously used to characterize the glutamate receptor binding with system Xc- raises some interesting interpretational issues regarding the mechanisms through which these analogues produce CNS damage. We are using a structure-based design approach to develop ligands to bind selectively to glutamate receptors and transporters, and will describe our progress.