| Description | 2-PMPA (2-(Phosphonomethyl)pentanedioic acid) is a potent and selective inhibitor of glutamate carboxypeptidase II (GCPII) (IC50=300 pM). |
| In vitro | 2-PMPA 是一种对 GCPII 具有强效和选择性的抑制剂。GCPII 是一种酶，能将丰富的神经肽N-乙酰天门冬氨酸-谷氨酸 (NAAG) 分解为 N-乙酰天门冬氨酸 (NAA) 和谷氨酸。2-PMPA 在多种神经疾病动物模型中显示出强大的疗效。2-PMPA 是一种高极性化合物，具有多个负电荷，这给生物基质中的分析带来了显著挑战[1]。2-PMPA 能减少氯胺酮引起的细胞活性降低及乳酸脱氢酶 (LDH) 水平增加，此效应在混合培养中观察到，但在神经元培养中未观察到[2]。 |
| In vivo | 经腹膜给予100 mg/kg 2-PMPA后，0.25小时达到血浆中的最大浓度275 μg/mL。其半衰期、曲线下面积、表观清除率和分布体积分别为0.64小时、210 μg×h/mL、7.93 mL/min/kg和0.44 L/kg[1]。2-PMPA以250 mg/kg剂量给药于麻醉小鼠后，初期升高后，灰质中的BOLD信号迅速下降并显著减弱。在167和250 mg/kg剂量下，2-PMPA对灰质中脑T2*信号的影响包括显著的初期上升，持续数分钟[3]。2-PMPA在脑卒中动物模型中表现出神经保护活性，在CCI模型中表现出抗痛觉过敏活性。给予2-PMPA（50 mg/kg）后，2-PMPA的平均峰值浓度为29.66±8.1 μM，该浓度约为抑制NAAG肽酶所需浓度的100,000倍，暗示其极佳的脑部渗透性。50 mg/kg 2-PMPA（i.p.）的给药可以造成细胞外NAAG浓度持续增加，该增加从给药后立即开始[4]。 |
| Cell experiments | Neuronal cultures and neuron–glia mixed cultures are treated with ketamine diluted in the culture medium (1, 3, 10, 30, 100, 300, 1000, 2000, 3000 μM) for 24 h to compare neurotoxicity in these two different cell cultures. 2-PMPA is selected to explore the protective effect on ketamine-induced neurotoxicity in these two different cell cultures. Cells are exposed to 2-PMPA (20, 50, 100 μM) half an hour before 10 μM ketamine treatment in neuronal cultures and 2 mM ketamine treatment in neuron–glia mixed cultures for 24 h. Different doses of ketamine chosen in neuronal cultures and neuron–glia mixed cultures are based on the results of cell viability tests[2]. |
| Target activity | GCP II:300 pM |
| Synonyms | 2-(Phosphonomethyl)pentanedioic acid |
| molecular weight | 226.12 |
| Molecular formula | C6H11O7P |
| CAS | 173039-10-6 |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year |
| Solubility | H2O: 28 mg/mL (123.83 mM) |
| References | 1. Rais R, et al. Bioanalytical method for evaluating the pharmacokinetics of the GCP-II inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA). J Pharm Biomed Anal. 2014 Jan;88:162-9. 2. Zuo D, et al. Existence of glia mitigated ketamine-induced neurotoxicity in neuron-glia mixed cultures of neonatal rat cortex and the glia-mediated protective effect of 2-PMPA. Neurotoxicology. 2014 Sep;44:218-30. 3. Baslow MH, et al. 2-PMPA, a NAAG peptidase inhibitor, attenuates magnetic resonance BOLD signals in brain of anesthetized mice: evidence of a link between neuron NAAG release and hyperemia. J Mol Neurosci. 2005;26(1):1-15. 4. Nagel J, et al. Effects of NAAG peptidase inhibitor 2-PMPA in model chronic pain-relation to brain concentration. Neuropharmacology. 2006 Dec;51(7-8):1163-71. |