Jackson P F, Cole D C, Slusher B S, Stetz S L, Ross L E, Donzanti B A, Trainor D A
Department of Medicinal Chemistry, ZENECA Pharmaceuticals, Wilmington, Delaware 19897, USA.
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.
为了研究一系列取代膦酸酯衍生物抑制神经肽酶N - 乙酰化α - 连接酸性二肽酶（NAALADase）的能力，设计并合成了这些化合物。结果表明这些分子可作为该酶的抑制剂，其中活性最强的（化合物3）的抑制常数（Ki）为0.275 nM。该化合物的活性比先前报道的该酶抑制剂高1000倍以上。NAALADase负责将丰富的神经肽N - 乙酰天冬氨酰谷氨酸（NAAG）分解为N - 乙酰天冬氨酸和谷氨酸。有人提出NAAG是谷氨酸受体亚群的神经递质；另外，也有人认为NAAG是突触谷氨酸的一种储存形式。因此，抑制NAALADase可能作为一种治疗手段用于那些认为与谷氨酸水平改变有关的疾病。
