Design of NAALADase inhibitors: A novel neuroprotective strategy

Excessive glutamatergic transmission is thought to be responsible for the i njury observed in a variety of neurological disorders such as stroke. N-ace tylaspartylglutamate (NAAG), a major peptidic component of the brain, has b een suggested to serve as a potential storage form of glutamate. N-acetylat ed-alpha -linked acidic dipeptidase (NAALADase, EC 3.4.17.21) is responsibl e for the hydrolysis of NAAG into N-acetylaspartate (NAA) and glutamate. If NAAG is a storage form of glutamate, then inhibition of NAAZ-ADase should be neuroprotective in diseases in which excess glutamatergic transmission i s detrimental. In addition, NAAG has been demonstrated to be an agonist at group II metabotropic glutamate receptors and functions as a mixed agonist/ antagonist at N-methyl-D-aspartate receptors. Therefore, inhibition of NAAL ADase would also function to increase NAAG levels which, in turn, should pr ovide neuroprotection via the interaction of NAAG with these receptors. Rec ently, potent and selective inhibitors of the enzyme have been designed and subsequently used to demonstrate that inhibition of NAALADase is neuroprot ective in animal models of neurodegeneration. As such, NAALADase inhibition represents a novel method of regulating extracellular glutamate levels and provides a new avenue for the treatment of neurological disorders.