Design, Synthesis, and Biological Activity of a Potent Inhibitor of the Neuropeptidase N-Acetylated α-Linked Acidic Dipeptidase

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 (compou...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1996-01, Vol.39 (2), p.619-622
Main Authors: Jackson, Paul F, Cole, Derek C, Slusher, Barbara S, Stetz, Susan L, Ross, Laurie E, Donzanti, Bruce A, Trainor, Diane Amy
Format: Article
Language:English
Subjects:
Acetylation
Animals
Biological and medical sciences
Central Nervous System - drug effects
Central Nervous System - enzymology
Central Nervous System - metabolism
Dipeptidases - antagonists & inhibitors
Dipeptidases - chemistry
Dipeptidases - metabolism
Dipeptides - metabolism
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Glutamate Carboxypeptidase II
Glutamatergic system (aspartate and other excitatory aminoacids)
Hydrogen-Ion Concentration
Medical sciences
Neuropeptides - metabolism
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Rats
Rats, Sprague-Dawley
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm950801q