L-Glutamine is the most abundant free amino acid in mammalian plasma (0.6 mM) and CSF (on.5 mM). In addition to protein synthesis, L- glutamine is well recognized for its involved in nitrogen homeostasis and general intermediary metabolism. It is, however, its role as the primary precursor for the CNS excitatory amino acid neurotransmitter L- glutamate that accounts for most of the recent interest in glutamine. It is the key intermediate in the glutamate cycle, a pathway credited with recycling synaptically released L-glutamate through the sequential action of the glial specific enzyme glutamine synthetase, and the neuronal enzyme glutaminase. For this cycle to function, there must also be efficient mechanisms for moving glutamate into glia, glutamine out of glia, and finally glutamine into neurons. While considerable progress has been made in identifying and pharmacologically manipulating the glutamate transporters, potent and selective inhibitors of the glutamine transporters remain elusive. The overall goal of this project is to characterize previously identified CNS sodium dependent glutamine transport systems ASC and N in cell lines, elucidate the pharmacological profile of these glutamine transport systems, and develop selective inhibitors as functional probes of these systems. The strategy to accomplish this is to design and synthesize a library of conformationally constrained amino acid analogues and to assay these compounds for inhibition of the glutamine transport systems. The use of conformationally constrained glutamate analogues was highly successful in defining he pharmacology of the excitatory amino acid (EAA) receptors and transporters. Analogously, a glutamine pharmacophore model using this approach will be developed for the transport systems ASC and N with the aid of computerized molecular modeling.
Showing the most recent 10 out of 137 publications
