DESIGN, SYNTHESIS, AND BIOLOGICAL-ACTIVITY OF A POTENT INHIBITOR OF THE NEUROPEPTIDASE N-ACETYLATED ALPHA-LINKED ACIDIC DIPEPTIDASE

A series of substituted phosphonate derivatives were designed and synt hesized in order to study the ability of these compounds to inhibit th e neuropeptidase N-acetylated alpha-linked acidic dipeptidase (NAALADa se). 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 c atabolism of the abundant neuropeptide N-acetyl-L-aspartylglutamate (N AAG) into N-acetylaspartate and glutamate. NAAG has been proposed to b e a neurotransmitter at a subpopulation of glutamate receptors; altern atively, 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 glutam ate are thought to be involved.