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 neurotransmitter and a potential neurotoxin within the mammalian central nervous system. Functionally juxtaposed between these neurophysiological and pathological actions are an assorted group of integral membrane transporter proteins that rapidly and efficiently sequester glutamate into cellular and subcellular compartments. While multiple systems exist that are capable of mediating the uptake of L-glutamate, the high-affinity, sodium-dependent transporters have emerged as the most prominent players in the CNS with respect to terminating the excitatory signal, recycling the transmitter, and regulating extracellular levels of glutamate below those which could induce excitotoxic pathology. The focus of the present review is on the pharmacological specificity of these sodium-dependent transporters and, more specifically, on 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 substituents to the carbon backbone of glutamate or aspartate (e.g., beta-hydroxyaspartate or methylglutamate derivatives) or the incorporation of ring systems (e.g., (carboxycyclopropyl)glycines, aminocyclobutane dicarboxylates, or pyrrolidine dicarboxylates), have been especially valuable in these efforts. In this review, a particular emphasis is placed on the identification of analogues that exhibit preferential activity among the recently cloned transporter subtypes and on the differentiation of substrates from non-transportable inhibitors.
Bridges
R J
RJ
Department of Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA. bridgesr@selway.umt.edu
Kavanaugh
M P
MP
Chamberlin
A R
AR
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001692:Biological Transport; D002490:Central Nervous System / Q000378:metabolism*; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D018377:Neurotransmitter Agents / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D018377:Neurotransmitter Agents; D001224:Aspartic Acid; D018698:Glutamic Acid; D012964:Sodium