Design of remarkably simple, yet potent urea-based inhibitors of glutamate carboxypeptidase II (NAALADase)
Design of remarkably simple, yet potent urea-based inhibitors of glutamate carboxypeptidase II (NAALADase)
复制标题
DOI：
10.1021/jm000406m
复制
发表时间：
2001-02-01
影响因子：
7.3
通讯作者：
Wroblewski, JT
中科院分区：
文献类型：
--
作者：
Kozikowski, AP;Nan, F;Wroblewski, JT
导言。氨基酸谷氨酸在哺乳动物的脑中含量很高，是中枢神经系统的主要兴奋性神经递质。谷氨酸通过对离子受体和代谢性受体的作用，在学习、记忆和发育可塑性等多种生理功能中发挥重要作用。谷氨酸受体的过度激活或细胞机制中保护免受生理性谷氨酸受体激活的不良后果的紊乱，已被认为与一系列神经疾病的发病机制有关。尽管在脑缺血的实验模型中，已有几种旨在减轻谷氨酸过度激活的病理后果的药物被证明可以减轻损伤，但到目前为止，这些化合物都没有被证明在中风的临床治疗中有效。N-乙酰-L-天冬氨酸-L-谷氨酸(NAAG)是一种广泛分布于哺乳动物神经系统的多肽类神经递质。2 NAAG既是代谢性谷氨酸受体(MGluR3)3的激动剂，也是N-甲基-D-天冬氨酸(NMDA)受体的混合型激动剂/拮抗剂。4-NAAG是由神经肽酶谷氨酸羧基肽酶II(GCPII；又称N-乙酰化R-连接酸性二肽酶，NAALADase，或NAAG多肽酶)在体外和体内降解，释放N-乙酰天冬氨酸和谷氨酸。因此，这种金属蛋白酶GCPII的作用被认为是双重的：(1)终止NAAG的神经递质活性；(2)释放谷氨酸，然后谷氨酸能够作用于各种谷氨酸受体亚型。在与谷氨酸能神经传递异常有关的疾病中，已经观察到GCPII和NAAG水平的变化。6根据这些发现，推测抑制GCPII可能通过增加NAAG水平，同时降低谷氨酸水平，为在脑缺血情况下实现神经保护提供一种有效的策略。事实上，Slusher等人最近的工作。结果表明，GCPII抑制剂2-PMPA对大鼠大脑中动脉短暂性闭塞(MCAO)后的损伤有显著的保护作用。此外，在大鼠MCAO模型中，2-PMPA降低谷氨酸水平，同时升高NAAG水平，正如可以预测的那样，化合物作为GCPII抑制剂发挥作用。作为一种治疗靶点，抑制GCPII被认为比基于受体的策略有潜在的好处，因为它代表了谷氨酸调节的上游机制，可以减少在许多谷氨酸能受体上的传递，而不是抑制单一受体亚型。8同样重要的是，NAAG与GABA和多巴胺等小胺递质共存于神经元中，并已被证明作用于突触前受体以调节递质释放。9.
Introduction. The amino acid glutamate is present in high concentrations in the mammalian brain, and it acts as the major excitatory neurotransmitter in the CNS. Through its actions on both ionotropic and metabotropic receptors, glutamate plays an important role in a variety of physiological functions including learning, memory, and developmental plasticity. Excessive activation of glutamate receptors or disturbances in the cellular mechanisms that protect against the adverse consequences of physiological glutamate receptor activation have been implicated in the pathogenesis of a host of neurological disorders. Although several drugs designed to attenuate the pathological consequences of excessive glutamate activation have been shown to reduce injury in experimental models of cerebral ischemia, so far none of these compounds has proven to be effective in the clinical treatment of stroke. 1 N-Acetyl-L-aspartyl-L-glutamate (NAAG) is a peptide neurotransmitter that is widely distributed in the mammalian nervous system. 2 NAAG is both an agonist at metabotropic glutamate receptors (mGluR3) 3 and a mixed agonist/antagonist at the N-methyl-D-aspartate (NMDA) receptor. 4 NAAG is hydrolyzed by the neuropeptidase glutamate carboxypeptidase II (GCPII; also known as N-acetylated R-linked acidic dipeptidase, NAALADase, or NAAG peptidase) to liberate N-acetylaspartate and glutamate both in vitro and in vivo. 5 The role of this metalloprotease GCPII is thus thought to be twofold:(1) to terminate the neurotransmitter activity of NAAG and (2) to liberate glutamate which is then able to act at the various glutamate receptor subtypes. Alterations in the levels of GCPII and NAAG have been observed in disorders that are linked to abnormalities in glutamatergic neurotransmission. 6 As a consequence of these findings, it has been hypothesized that the inhibition of GCPII might provide an effective strategy for achieving neuroprotection in cases of cerebral ischemia by increasing the levels ofNAAG while decreasing the levels of glutamate. In fact, recent work by Slusher et al. led to the demonstration that the GCPII inhibitor 2-PMPA provides significant protection against injury in rats after transient middle cerebral artery occlusion (MCAO). 7 Furthermore, in the rat MCAO model, 2-PMPA decreased glutamate levels while increasing NAAG levels, as would be predicted for a compound working as a GCPII inhibitor. As a therapeutic target, GCPII inhibition has been suggested to have potential benefits over receptor-based strategies, as it represents an upstream mechanism of glutamate regulation that could reduce transmission at a number of glutamatergic receptors rather than inhibiting a single receptor subtype. 8 Equally important, NAAG is colocalized in neurons with small amine transmitters including GABA and dopamine, and it has been shown to act on presynaptic receptors to regulate transmitter release. 9