2-PMPA

2023-10-03:

2-PMPA #

• Noname is doing a groupbuy of a prodrug for it, which he’s calling PBIO-21.
  • It’s something like tris-POC-2-PMPA, tris-POM-2-PMPA or some other PMPA prodrug
  • Enhanced Oral Bioavailability of 2-(Phosphonomethyl)-pentanedioic Acid (2-PMPA) from its (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL)-Based Prodrugs
  • γ-PAB-2-PMPA is also potentially a good form
• GCP-II inhibitor.
  • Btw, this might make it really interesting with psychedelics. Might offset cognitive impairment.
• Inhibition of N-acetylated-alpha-Linked-Acidic Dipeptidase (NAALADase) by 2-PMPA Attenuates Cocaine-Induced Relapse in Rats: A NAAG-mGluR2/3-Mediated Mechanism
  • Dose-dependently lowered extracellular DA and glutamate in the NAc.
• Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration
• The prodrug is also to be administered intranasally as well:
  • A y-ESTER prodrug of 2-PMPA delivered IN managed to increase 2-PMPA in the body by 40-80 fold
• 
  • The thiol-containing struxture on 2-MPPA makes it have immunogenicity
• Decreases extracellular glutamate.
• Neuroprotection produced by the NAALADase inhibitor 2-PMPA in rat cerebellar neurons
  • Using neuron-enriched primary cultures derived from rat embryo (E15) cerebellum, 2-PMPA afforded 100% neuroprotection from injuries induced by hypoxia
  • In contrast, against glutamate or N-methyl-D-aspartate (NMDA) injury, 2-PMPA was less potent and its efficacy limited to a maximum of 46% and 16%, respectively.
  • glutamate (NAAG) was neuroprotective against all four injury mechanisms and compared to 2-PMPA, exhibited a different “phosphate effect” on neuroprotection.
• Effects of N-acetylaspartylglutamate (NAAG) peptidase inhibition on release of glutamate and dopamine in prefrontal cortex and nucleus accumbens in phencyclidine model of schizophrenia
  • Reduced PCP-induced increases in glutamate and dopamine levels in the medial prefrontal cortex and nucleus accumbens. (As did ZJ43)
  • Blocked PCP-induced increases in glutamate but not dopamine or its metabolites (… in in vitro neurons?)
• We’ve got some off-target effects. Really gotta ask noname about this one. Identification of 2-PMPA as a novel inhibitor of cytosolic carboxypeptidases: Inhibits CCP1 (aka Nna1). See for instance:
  • Nna1, Essential for Purkinje Cell Survival, Is also Associated with Emotion and Memory
    • Nna1N KO mice revealed a reduced level of the AMPA-type glutamine receptor GluA2 in the hippocampal synaptosomal fraction. In addition, the motor protein kinesin-1, which transports GluA2 to dendrites, was also decreased. Ki = 0.11 μM!
    • Although the Nna1N KO mice showed no severe cerebellar phenotypes, such as Purkinje cell death, they exhibited a variety of phenotypes in systematic behavioral analyses, such as hyperactivity, reduced anxiety-like behavior, and impaired memory learning. These findings indicate that Nna1 is involved not only in neuronal survival but also in higher brain functions related to emotion and memory.
  • The 2S form that noname is synthesizing has much less of an affinity for this.
• Nomame says GCP-II inhibition will be a lot like NAC in its anti-addictive effects.