Progress in the discovery and development of glutamate carboxypeptidase II inhibitors

Tsukamoto, Takashi; Wozniak, Krystyna M.; Slusher, Barbara S.

doi:10.1016/j.drudis.2007.07.010

Cited by 92 publications

(95 citation statements)

References 85 publications

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“…carbonyl]-L-glutamic acid) was provided by Alan Kozikowski (41), and 2-(phosphonomethyl)pentane-1,5-dioic acid (2-PMPA) (22) and the mGluR2/3 antagonist LY341495 (42) were from Tocris Cookson Ltd. (Bristol, UK). PCP was from SigmaAldrich.…”

Section: Methodsmentioning

confidence: 99%

Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia

Zuo

Bzdega

Olszewski

et al. 2012

Journal of Biological Chemistry

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Background: Inhibitors of the enzyme that inactivates the peptide transmitter N-acetylaspartylglutamate reduce behaviors induced by PCP in animal models of schizophrenia. Results: NAAG peptidase inhibition reduces PCP-induced glutamate release in two brain areas implicated in this disorder. Conclusion: Peptidase-mediated inhibition of glutamate release is consistent with the glutamate model of this disorder. Significance: NAAG peptidase inhibitors warrant further biochemical characterization as potential antipsychotic drugs.

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Section: Methodsmentioning

confidence: 99%

Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia

Zuo

Bzdega

Olszewski

et al. 2012

Journal of Biological Chemistry

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“…mGluR3s are expressed on the surface of presynaptic neurons and astrocytes in the CNS. Activation of mGluR3s by NAAG reduces cAMP and cGMP levels, inhibits glutamate release, and stimulates a release of transforming growth factor beta (1,2). A recent study reported impaired performance on spatial reference and working memory tasks in mGluR2/3 knockout mice (3), suggesting a role for group II mGluRs in cognitive function.…”

mentioning

confidence: 99%

“…1) (1, 2). NAAG, the most abundant neuropeptide in the mammalian brain, is a selective agonist for metabotropic glutamate receptor 3 (mGluR3) (1,2). mGluR3s are expressed on the surface of presynaptic neurons and astrocytes in the CNS.…”

mentioning

confidence: 99%

Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

Rahn

Watkins

Alt³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Half of all patients with multiple sclerosis (MS) experience cognitive impairment, for which there is no pharmacological treatment. Using magnetic resonance spectroscopy (MRS), we examined metabolic changes in the hippocampi of MS patients, compared the findings to performance on a neurocognitive test battery, and found that N-acetylaspartylglutamate (NAAG) concentration correlated with cognitive functioning. Specifically, MS patients with cognitive impairment had low hippocampal NAAG levels, whereas those with normal cognition demonstrated higher levels. We then evaluated glutamate carboxypeptidase II (GCPII) inhibitors, known to increase brain NAAG levels, on cognition in the experimental autoimmune encephalomyelitis (EAE) model of MS. Whereas GCPII inhibitor administration did not affect physical disabilities, it increased brain NAAG levels and dramatically improved learning and memory test performance compared with vehicle-treated EAE mice. These data suggest that NAAG is a unique biomarker for cognitive function in MS and that inhibition of GCPII might be a unique therapeutic strategy for recovery of cognitive function.G lutamate carboxypeptidase II (GCPII), previously called Nacetylated-α-linked acidic dipeptidase (NAALADase), is a membrane-bound enzyme expressed on the surface of astrocytes that catalyzes the cleavage of N-acetylaspartylglutamate (NAAG) into N-acetylaspartate (NAA) and glutamate ( Fig. 1) (1, 2). NAAG, the most abundant neuropeptide in the mammalian brain, is a selective agonist for metabotropic glutamate receptor 3 (mGluR3) (1, 2). mGluR3s are expressed on the surface of presynaptic neurons and astrocytes in the CNS. Activation of mGluR3s by NAAG reduces cAMP and cGMP levels, inhibits glutamate release, and stimulates a release of transforming growth factor beta (1, 2). A recent study reported impaired performance on spatial reference and working memory tasks in mGluR2/3 knockout mice (3), suggesting a role for group II mGluRs in cognitive function.Cognitive impairment is a frequent comorbidity of many neurological diseases, including multiple sclerosis (MS). MS affects over 2 million individuals worldwide, and ∼40-65% of all MS patients experience cognitive impairment (4). The most commonly and severely affected facets of cognition in MS patients are anterograde episodic memory, working memory, and processing speed (5-7), and these impairments strongly contribute to the high frequency of unemployment in MS patient populations (8). Global brain atrophy, candidate genetic risk factors, accelerated inflammatory processes (7), and dysregulated signaling pathways (9) have been implicated as contributing factors, but an incomplete understanding of the molecular mechanisms behind cognitive impairment in MS has prevented the development and Food and Drug Administration (FDA) approval of drug therapies.The most widely used animal model of MS, experimental autoimmune encephalomyelitis (EAE), is a valuable tool for developing treatments for MS. Three FDA-approved disease-modifying agents were deve...

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“…Although its role in the progression of prostate cancer remains conjectural, there is emerging evidence that GCP II plays a regulatory role in angiogenesis 5 . Various chemical scaffolds have been developed as inhibitors of this enzyme to selectively deliver imaging and therapeutic agents [6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

A method to determine the mode of binding for GCPII inhibitors using bio-layer interferometry

Choy

Berkman

2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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The rapid dilution of the enzyme-inhibitor complex assay to monitor the recovery of enzyme activity is a well-established assay to determine the reversibility of inhibition. Our laboratory has previously employed this method to ascertain the reversibility of known glutamate carboxypeptidase II (GCPII)-targeting agents. Due to the tedious and time-consuming nature of the assay, we sought to develop a facile method to determine the reversibility of wellcharacterized GCPII inhibitors using bio-layer interferometry (BLI). The results from the BLI assay are in agreement with the rapid dilution method. Herein, we report for the first time, a rapid, novel real-time BLI method to determine reversibility of inhibition.

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Progress in the discovery and development of glutamate carboxypeptidase II inhibitors

Cited by 92 publications

References 85 publications

Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia

Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia

Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

A method to determine the mode of binding for GCPII inhibitors using bio-layer interferometry

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