Research in the Bridges laboratory focuses on the transport systems responsible for mediating the uptake and sequestration of the excitatory neurotransmitter glutamate. Using conformationally constrained analogues of this acidic amino acid, Bridges and his associates probe the pharmacological specificity and the physiologically roles of these transporters in the brain and spinal cord. This work employs a wide range of experimental systems (e.g., subcellular preparations, primary tissue culture, cell lines expressing cloned transporters) and approaches (e.g., molecular modeling, organic synthesis, radiotracer flux, HPLC, radioligand autoradiography).

Elucidating how the levels of this excitatory neurotransmitter are regulated in the central nervous system is critical to understanding both glutamate-mediated neuronal signaling and glutamate-mediated neuropathology. Cellular transporters rapidly translocate extracellular glutamate into neurons and glia, potentially contributing to signal termination, the recycling of the neurotransmitter, and the maintenance of sub-pathological levels of glutamate. Another glutamate transporter, distinct from the cellular system, is present on synaptic vesicles and serves to concentrate glutamate in these vesicles prior to its release during excitatory neurotransmission.

Work in the laboratory has led to the discovery of several potent and specific inhibitors of the cellular glutamate transporters. In addition to their utility in modeling the binding sites on these proteins, these compounds have been exploited in a number of physiological preparations to investigate the consequences of impaired function. Further, considerable progress has been made in developing compounds that differentiate the processes of binding and translocation, as well exhibit selectivity among the different subclasses of cellular transporters. Recent progress has also been made in identifying a number of new inhibitors of the glutamate transporter present on synaptic vesicles. As few inhibitors have been identified for this uptake system, these compounds should be particularly valuable in investigating mechanisms underlying glutamate-mediated neurotransmission.

Other research in the group involves using conformationally constrained glutamate analogues as probes of the excitatory amino acid receptors and receptor-mediated neuronal pathology. The Bridges lab also maintains active collaborations with research groups at a number of universities including the University of California at Irvine, King's College London, and the Vollum Institute at the Oregon Health Science University.

Willis, C.L., Wacker, D.A., Bartlett, R.D., Bleakman, D., Lodge, D., Chamberlin, A.R., and Bridges, R.J.  Irreversible inhibition of high affinity 3H-kainate binding by a novel photoactivatable analogue: ((2'S,3'S,4'R)-2'-carboxy-4'-(2-diazo-1-oxo-3,3,3-trifluoropropyl)-3'-prrrolidinylacetate. J. Neurochem. 68:1503, 1997.

Willis, C.L., Dauenhauer, D., Humphrey, J.M., Chamberlin, A.R., Buller, A.L., Monaghan, D.T., and Bridges, R.J. Methylation of the NMDA receptor agonist L-trans-2,3-pyrrolidine-dicarboxylate; enhanced excitotoxic potency and selectivity. Toxicol. App. Pharmacol. 144:45, 1997.

Wacker, D.A., Lovering, F.E., Bridges, R.J., Willis, C.L., Bartlett, R.D., Chamberlin, A.R. (1997) A selective photoaffinity ligand for the kainate class of excitatory amino acid receptor. Syn Lett. Corey Issue, 503, 1997.

Chamberlin, A.R., Koch, H.P., and Bridges, R.J. Design and synthesis of conformationally constrained inhibitors of the high-affinity, sodium-dependent glutamate transporters. In Methods in Enzymology, (S. Amara, ed) Academic Press, NY, NY (in press).

Bartlett, R.D., Esslinger, C.S., Thompson, C.M., and Bridges, R.J. Substituted quinolines as inhibitors of L-Glutamate transport into synaptic vesicles. Neuropharm. (in press)

Esslinger, C.S., Koch, H.P., Chamberlin, A.R., Bridges, R.J., and Thompson, C.M.   Synthesis and inhibitory activity of meso-2,4-methano-2,4-pyrrolidine dicarboxylate: a conformationally locked glutamate transporter inhibitor. Bioorg. Med. Chem. Lett. (in press).