2-(Phosphonomethyl)-pentanedioic Acid

2-(Phosphonomethyl)-pentanedioic acid (2-PMPA) is a potent inhibitor of glutamate carboxypeptidase II (GCP II), also known as N-acetylated α-linked dipeptidase (NAALADase), with a K_i value of 98 pM for release of glutamate from the NAALADase peptide substrate N-acetylasparatylglutamate (NAAG).¹ It is selective for GCP II/NAALADase over a panel of 100 receptors, transporters, ion channels, and enzymes at a concentration of 10 μM.² 2-PMPA is neuroprotective against hypoxia (EC₅₀ = 8.4 μM), but not veratridine-induced injury, in neuron-enriched primary cultures from rat embryo cerebellum.³ In vivo, 2-PMPA reduces neuronal cell death induced by middle cerebral artery occlusion via increases in NAAG expression and reduction of glutamate in rats.² 2-PMPA (100 mg/kg) blocks the conditioned place preference response to cocaine, but not food, in male rats.⁴ It reduces the number of flinches induced by formalin injection into the footpad of mice when administered at a dose of 10 μg per animal, an effect that is reversed by the group II metabotropic glutamate receptor antagonist LY341495.⁵ 2-PMPA also decreases severity and delays onset of experimental autoimmune encephalomyelitis (EAE) in mice.⁶

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1. Luthi-Carter, R., Barczak, A.K., Speno, H., et al. Hydrolysis of the neuropeptide N-acetylaspartylglutamate (NAAG) by cloned human glutamate carboxypeptidase II. Brain Res. 795(1-2), 341-348 (1998).

2. Slusher, B.S., Vornov, J.J., Thomas, A.G., et al. Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury. Nat. Med. 5(12), 1396-1402 (1999).

3. Tortella, F.C., Lin, Y., Ved, H., et al. Neuroprotection produced by the NAALADase inhibitor 2-PMPA in rat cerebellar neurons. Eur. J. Pharmacol. 402(1-2), 31-37 (2000).

4. Slusher, B.S., Thomas, A., Paul, M., et al. Expression and acquisition of the conditioned place preference response to cocaine in rats is blocked by selective inhibitors of the enzyme N-acetylated-α-linked-acidic dipeptidase (NAALADASE). Synapse 41(1), 22-28 (2001).

5. Yamamoto, T., Kozikowski, A., Zhou, J., et al. Intracerebroventricular administration of N-acetylaspartylglutamate (NAAG) peptidase inhibitors is analgesic in inflammatory pain. Mol. Pain 4:31, (2008).

6. Ha, D., Bing, S.J., Ahn, G., et al. Blocking glutamate carboxypeptidase II inhibits glutamate excitotoxicity and regulates immune responses in experimental autoimmune encephalomyelitis. FEBS J. 283(18), 3438-3456 (2016).