2-PMPA stands out as a highly effective and specific GCPII inhibitor, an enzyme responsible for breaking down the widely present neuropeptide NAAG into NAA and glutamate, with IC50 value of 300 pM. It has shown considerable success in a variety of animal models for neurological disorders. Due to its high polarity and several negative charges, 2-PMPA presents substantial analytical challenges in biological matrices[1]. 2-PMPA mitigates the reduction in cell viability and the elevation of LDH levels caused by ketamine in mixed cell cultures, while these effects are not observed in neuronal cultures alone[2].
2-PMPA 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
C4-2 prostate cancer xenograft model
Intravenous injection
3 mg/kg
Single dose
Evaluate the preferential delivery of 2-PMPA to salivary glands and kidneys by JHU-2545, showing significantly higher 2-PMPA exposure in kidneys and salivary glands with minimal effect on tumor.
Eur J Nucl Med Mol Imaging. 2025 Apr;52(5):1631-1641
Mice
DSS-induced colitis model and IL-10−/− spontaneous colitis model
Intraperitoneal injection
100 mg/kg
Once daily for 7 days (DSS model) or 3 weeks (IL-10−/− model)
2-PMPA significantly improved disease activity index, colon weight, colon length, and histopathological scores in both DSS-induced colitis and IL-10?/? spontaneous colitis models.
JCI Insight. 2016 Aug 4;1(12):e88634
Rats
Cocaine self-administration and brain-stimulation reward model
Intraperitoneal injection
10, 30, 100 mg/kg
Single administration, 30 minutes pretreatment
2-PMPA significantly inhibited cocaine self-administration and cocaine-enhanced brain-stimulation reward, and these effects were blocked by the mGlu2/3 receptor antagonist LY341495.
Neuropharmacology. 2010 Jan;58(1):304-13
Mice
TNBS-induced colitis model
Enema administration
2.5 mg/mL
Once daily for 3 days
To evaluate the therapeutic effect of 2-PMPA in the TNBS-induced colitis model, results showed that 2-PMPA significantly ameliorated macroscopic and microscopic symptoms of colitis.
J Control Release. 2017 Oct 10;263:132-138
BALB/c nude mice
LS174T-PSMA and LNCaP xenograft models
Intravenous injection
50 nmol
Single injection
To evaluate the inhibitory effect of 2-PMPA on renal uptake and its impact on tumor/kidney radioactivity ratios
Theranostics. 2016 Apr 12;6(6):849-61
2-PMPA 动物研究
Animal study
Following intraperitoneal injection at a dose of 100 mg/kg, 2-PMPA reaches a peak plasma concentration of 275 μg/mL within 0.25 hours. Its pharmacokinetic parameters include a half-life of 0.64 hours, an area under the curve (AUC) of 210 μg×h/mL, an apparent clearance rate of 7.93 mL/min/kg, and a volume of distribution of 0.44 L/kg[1]. Administered at a dosage of 250 mg/kg in an anesthetized mouse, 2-PMPA causes an initial increase followed by a swift reduction and notable decrease in BOLD signals within the gray matter. The impact of 2-PMPA on the brain's T2* signals in gray matter, at dosages of both 167 and 250 mg/kg, is characterized by a substantial initial elevation that persists for several minutes[3]. 2-PMPA exhibits neuroprotective effects in a stroke animal model and anti-allodynic properties in the CCI model. When administered at 50 mg/kg, 2-PMPA achieves a mean peak plasma concentration of 29.66±8.1 μM, which is substantially higher—by approximately 100,000 times—than the amount required to inhibit NAAG peptidase, suggesting excellent brain penetration. The administration of 2-PMPA at this dosage leads to a progressive increase in extracellular NAAG levels, beginning immediately after administration[4].
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