Design, synthesis, and biological activity of a potent inhibitor of the neuropeptidase N-acetylated α-linked acidic dipeptidase

Paul F. Jackson, Derek C. Cole, Barbara Slusher, Susan L. Stetz, Laurie E. Ross, Bruce A. Donzanti, Diane Amy Trainor

Research output: Contribution to journalArticle

Abstract

A series of substituted phosphonate derivatives were designed and synthesized in order to study the ability of these compounds to inhibit the neuropeptidase N-acetylated α-linked acidic dipeptidase (NAALADase). The molecules were shown to act as inhibitors of the enzyme, with the most potent (compound 3) having a K(i) of 0.275 nM. The potency of this compound is more than 1000 times greater than that of previously reported inhibitors of the enzyme. NAALADase is responsible for the catabolism of the abundant neuropeptide N-acetyl-L-aspartylglutamate (NAAG) into N-acetylaspartate and glutamate. NAAG has been proposed to be a neurotransmitter at a subpopulation of glutamate receptors; alternatively, NAAG has been suggested to act as a storage form of synaptic glutamate. As a result, inhibition of NAALADase may show utility as a therapeutic intervention in diseases in which altered levels of glutamate are thought to be involved.

Original languageEnglish (US)
Pages (from-to)619-622
Number of pages4
JournalJournal of Medicinal Chemistry
Volume39
Issue number2
DOIs
StatePublished - Jan 19 1996
Externally publishedYes

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aspartylglutamate
Bioactivity
Glutamic Acid
Enzyme Inhibitors
Organophosphonates
Glutamate Receptors
Neuropeptides
Neurotransmitter Agents
Derivatives
Molecules
dipeptidase

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Design, synthesis, and biological activity of a potent inhibitor of the neuropeptidase N-acetylated α-linked acidic dipeptidase. / Jackson, Paul F.; Cole, Derek C.; Slusher, Barbara; Stetz, Susan L.; Ross, Laurie E.; Donzanti, Bruce A.; Trainor, Diane Amy.

In: Journal of Medicinal Chemistry, Vol. 39, No. 2, 19.01.1996, p. 619-622.

Research output: Contribution to journalArticle

Jackson, Paul F. ; Cole, Derek C. ; Slusher, Barbara ; Stetz, Susan L. ; Ross, Laurie E. ; Donzanti, Bruce A. ; Trainor, Diane Amy. / Design, synthesis, and biological activity of a potent inhibitor of the neuropeptidase N-acetylated α-linked acidic dipeptidase. In: Journal of Medicinal Chemistry. 1996 ; Vol. 39, No. 2. pp. 619-622.
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AU - Donzanti, Bruce A.

AU - Trainor, Diane Amy

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