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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