Design of NAALADase inhibitors: A novel neuroprotective strategy

Paul F. Jackson, Barbara Slusher

Research output: Contribution to journalArticle

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-α-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.

Original languageEnglish (US)
Pages (from-to)949-957
Number of pages9
JournalCurrent Medicinal Chemistry
Volume8
Issue number8
StatePublished - 2001
Externally publishedYes

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Glutamate Carboxypeptidase II
Glutamic Acid
Nervous System Diseases
Metabotropic Glutamate Receptors
Enzyme Inhibitors
N-Methyl-D-Aspartate Receptors
N-acetyl-1-aspartylglutamic acid
Hydrolysis
Brain
Animals
Animal Models
Stroke
Wounds and Injuries

ASJC Scopus subject areas

  • Organic Chemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Pharmacology

Cite this

Design of NAALADase inhibitors : A novel neuroprotective strategy. / Jackson, Paul F.; Slusher, Barbara.

In: Current Medicinal Chemistry, Vol. 8, No. 8, 2001, p. 949-957.

Research output: Contribution to journalArticle

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