Substrate inhibitors and blockers of excitatory amino acid transporters in the treatment of neurodegeneration: critical considerations

Excessive glutamate release (mediated by reversed uptake) or impaired reuptake contributes to the etiopathology of many neurodegenerative disorders. Thus great effort has been devoted to the discovery of agents that can interfere with high-affinity Na+-dependent glutamate transport, with the aim of finding new therapeutics against neurodegenerative diseases. We developed two different 3D-pharmacophore models for substrate inhibitors and blockers, which led to the rational design of novel and potent glutamate and aspartate analogues that selectively interact with excitatory amino acid transporters (EAAT). Our results indicated that all analysed EAAT ligands share the same orientation of the acidic functions and the protonatable nitrogen, even though the distance between the carboxylic carbons varies from 3.7 to 4.9 A. This distance does not discriminate between substrate inhibitors and blockers, but between glutamate and aspartate derivatives. In contrasts differences in the volume distribution of the rest of the molecule with respect to the axis connecting the two carboxylic groups are responsible for the difference in activity between transportable and nontransportable inhibitors. Thus our 3D receptor interaction model for EAAT substrates and nontransportable inhibitors could lead to the rational design of selective EAAT ligands as possible neuroprotective agents. However, some critical points, such as which glutamate transporter is present on glutamatergic nerve terminals and which glutamate transporter mediates reversed glutamate uptake, still remain to be elucidated.