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

J Med Chem. 1996 Jan 19;39(2):619-22. doi: 10.1021/jm950801q.


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 alpha-linked acidic dipeptidase (NAALADase). The molecules were shown to act as inhibitors of the enzyme, with the most potent (compound 3) having a Ki 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-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.

MeSH terms

  • Acetylation
  • Animals
  • 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
  • Hydrogen-Ion Concentration
  • Neuropeptides / metabolism
  • Rats
  • Rats, Sprague-Dawley


  • Dipeptides
  • Enzyme Inhibitors
  • Neuropeptides
  • isospaglumic acid
  • Dipeptidases
  • Glutamate Carboxypeptidase II