Abstract
Excessive glutamatergic transmission is thought to be responsible for the injury observed in a variety of neurological disorders such as stroke. N-acetylaspartylglutamate (NAAG), a major peptidic component of the brain, has been suggested to serve as a potential storage form of glutamate. N-acetylated-a-linked acidic dipeptidase (NAALADase, EC 3.4.17.21) is responsible for the hydrolysis of NAAG into N-acetylaspartate (NAA) and glutamate. If NAAG is a storage form of glutamate, then inhibition of NAALADase should be neuroprotective in diseases in which excess glutamatergic transmission is 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 NAALADase would also function to increase NAAG levels which, in turn, should provide neuroprotection via the interaction of NAAG with these receptors. Recently, potent and selective inhibitors of the enzyme have been designed and subsequently used to demonstrate that inhibition of NAALADase is neuroprotective 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.
Keywords: NAALADase Inhibitors, Neuroprotective Strategy, glutamatergic transmission, N-acetylaspartylglutamate NAAG, N-acetylated-a-linked acidic dipeptidase NAALADase, N-acetylaspartate, NAALADase INHIBITOR, PHOSPHORUS
Current Medicinal Chemistry
Title: Design of NAALADase Inhibitors A Novel Neuroprotective Strategy
Volume: 8 Issue: 8
Author(s): Paul F. Jackson and Barbara S. Slusher
Affiliation:
Keywords: NAALADase Inhibitors, Neuroprotective Strategy, glutamatergic transmission, N-acetylaspartylglutamate NAAG, N-acetylated-a-linked acidic dipeptidase NAALADase, N-acetylaspartate, NAALADase INHIBITOR, PHOSPHORUS
Abstract: Excessive glutamatergic transmission is thought to be responsible for the injury observed in a variety of neurological disorders such as stroke. N-acetylaspartylglutamate (NAAG), a major peptidic component of the brain, has been suggested to serve as a potential storage form of glutamate. N-acetylated-a-linked acidic dipeptidase (NAALADase, EC 3.4.17.21) is responsible for the hydrolysis of NAAG into N-acetylaspartate (NAA) and glutamate. If NAAG is a storage form of glutamate, then inhibition of NAALADase should be neuroprotective in diseases in which excess glutamatergic transmission is 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 NAALADase would also function to increase NAAG levels which, in turn, should provide neuroprotection via the interaction of NAAG with these receptors. Recently, potent and selective inhibitors of the enzyme have been designed and subsequently used to demonstrate that inhibition of NAALADase is neuroprotective 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.
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Jackson F. Paul and Slusher S. Barbara, Design of NAALADase Inhibitors A Novel Neuroprotective Strategy, Current Medicinal Chemistry 2001; 8 (8) . https://dx.doi.org/10.2174/0929867013372797
DOI https://dx.doi.org/10.2174/0929867013372797 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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