Can selective ligands for glutamate binding proteins be rationally designed?
A major neurotransmitter, L-Glutamate must be stored, transported and received, and these processes are mediated by proteins that bind this simple yet essential amino acid. Detailed evidence continues to emerge on the structure of Glu binding proteins, which includes both receptors and transporters. It appears that receptors and transporters bind to Glu in different conformations, which may present a pharmacological opportunity. This review will compare and contrast information available on Glu Receptors (AMPA, NMDA, KA and mGlu), excitatory amino acid transporters (EAATs), the system Xc- transporter (XCT) and the vesicular Glutamate transporter (GVT). The cross-reactivity of ligands which have been previously used to characterize the glutamate binding proteins with system Xc- raises some fundamental interpretational issues regarding the mechanisms through which these analogues produce CNS damage. Although at one time it was thought that unraveling selectivity among glutamate binding proteins was an intractable problem, recently the NMDA antagonist (memantine) has been approved for general medical practice for treatment of Alzheimer's disease. Two other agents are in advanced clinical trials: an Ampakine for potential improvement of cognitive disorders, and a selective mGlu agonist for treatment of anxiety. The prospects for unraveling cross-reactivity will be weighed in light of a critical comparison of the glutamate binding protein targets.
Natale
Nicholas R
NR
301 Renfrew Hall, Department of Chemistry, University of Idaho, Moscow, ID 83844-2343 USA. nrnatale@uidaho.edu
Magnusson
Kathy R
KR
Nelson
Jared K
JK
D027182:Amino Acid Transport System y+ / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D015195:Drug Design; D050491:Glutamate Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000378:metabolism; D008024:Ligands; D008956:Models, Chemical; D017470:Receptors, Glutamate / Q000737:chemistry / Q000378:metabolism*; D050496:Vesicular Glutamate Transport Proteins / Q000737:chemistry / Q000378:metabolism*
D027182:Amino Acid Transport System y+; D050491:Glutamate Plasma Membrane Transport Proteins; D007555:Isoxazoles; D008024:Ligands; D017470:Receptors, Glutamate; C118895:SLC7A11 protein, human; C492255:Slc7a11 protein, mouse; D050496:Vesicular Glutamate Transport Proteins; D018698:Glutamic Acid