SYNTHESIS OF NB-946;-ARYL-ASPARTAMIDES, Na-945;-ARYLAMIDE-ASPARTATES, AND HYDROXY-L-PROLINE DERIVATIVES AS INHIBITORS OF AMINO ACID TRANSPORT FOR EVALUATING THE GLUTAMINE / GLUTAMATE CYCLE
The glutamate / glutamine cycle is most traditionally described as the recycling of L-glutamate and L-glutamine via a concerted effort by a variety of cell membrane spanning amino acid transporters and amino acid converting enzymes, glutaminase and glutamine synthetase. This work details the design and synthesis of amino acid analogs, based off of an L-aspartate or L-proline scaffold, to be evaluated as inhibitors of the amino acid transporters ASCT (subtypes 1 & 2) and the excitatory amino acid transporters EAATs (subtypes 1-3), both involved in the glutamate / glutamine cycle. Furthermore, we have identified a number of potent substrate and nonsubstrate inhibitors of the ASCT and EAAT transporters by electrophysiological and radiolabeled uptake screening. Computational modeling of the synthesized analogs docked into a homology structure suggests a conformational bias that is indeed supported by the pharmacologic activity of our lead compounds. These novel pharmacologic leads will be applied in the design and synthesis of a new generation of inhibitors with greater potency and selectivity towards these transporters of interest.
© Copyright 2011 Brent Russell Lyda