A pharmacological review of competitive inhibitors and substrates of high-affinity, sodium-dependent glutamate transport in the central nervous system

The acidic amino acid L-glutamate acts as both a primary excitatory neurotr ansmitter and a potential neurotoxin within the mammalian central nervous s ystem. Functionally juxtaposed between these neurophysiological and patholo gical actions are an assorted group of integral membrane transporter protei ns that rapidly and efficiently sequester glutamate into cellular and subce llular compartments. While multiple systems exist that are capable of media ting the uptake of L-glutamate, the high-affinity, sodium-dependent transpo rters have emerged as the most prominent players in the CNS with respect to terminating the excitatory signal, recycling the transmitter, and regulati ng extracellular levels of glutamate below those which could induce excitot oxic pathology. The focus of the present review is on the pharmacological s pecificity of these sodium-dependent transporters and, more specifically, o n the competitive inhibitors that have been used to delineate the chemical requirements for binding and translocation. Analogues of glutamate that are conformationally constrained as a consequence of either the addition of su bstituents to the carbon backbone of glutamate or aspartate (e.g., beta-hyd roxyaspartate or methylglutamate derivatives) or the incorporation of ring systems (e.g., (carboxycyciopropyl)glycines, aminocyclobutane dicarboxylate s, or pyrrolidine dicarboxylates), have been especially valuable in these e fforts. In this review, a particular emphasis is placed on the identificati on of analogues that exhibit preferential activity among the recently clone d transporter subtypes and on the differentiation of substrates from non-tr ansportable inhibitors.