N-Acetyl-L-aspartyl-L-glutamate (NAAG 69) is a highly prevalent small peptide neutotransmitter that is suggested to act as an endogenous agonist at group II mGluR receptors.70 NAAG is catabolized to N-acetylaspartate and glutamate by NAAG peptidases glutamate carboxypeptidase II and III localized to the extracellular surface of astrocytes.
As discussed above, activators of the group II mGluRs hold promise as novel antipsychotics. Therefore, it has been suggested that inhibitors of NAAG peptidase could increase the levels of NAAG and provide antipsychotic efficacy through the activation of group II mGluRs.71 A number of potent and selective NAAG peptidase inhibitors have been discovered, including 2-PMPA 70, the more potent analog GPI-5693 71, and the structurally distinct ZJ38 72. The ability to selectively target these enzymes provides an opportunity to explore potential efficacy in animal models of schizophrenia.
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