NAAG was discovered as a nervous system-specific peptide in 1965 by Curatolo and colleagues[3] but initially disregarded as a neurotransmitter and not extensively studied.

This can lead to several changes in the cellular activity, including regulation of gene expression, reduction in the release of transmitter, and inhibition of long-term potentiation.

Since other neuropeptides and nearly all vertebrate peptides are synthesized by post-translational processing, NAAG synthetase activity is relatively unique.

Two main types of inhibitors of this enzyme are known: compounds related to 2-(phosphonomethyl)pentanedioic acid (2-PMPA) and urea-based analogs of NAAG, including ZJ43, ZJ17, and ZJ11.

This elevated NAAG gives greater activation of presynaptic mGluR3 receptors, which decrease release of transmitter (glutamate) in the pain signaling pathways of the spinal cord and brain.

To model schizophrenia, animals were injected with phencyclidine (PCP) and, therefore, exhibited symptoms of the disorder, such as social withdrawal and motor responses.

Upon injection with ZJ43, these behaviors were decreased, suggesting that an increase in NAAG in the synapse — and its subsequent activation of mGluR3 receptors — has potential as a co-therapy for schizophrenia.

Neale JH, Yamamoto T. (2020) "N-acetylaspartylglutamate (NAAG) and glutamate carboxypeptidase II: An abundant peptide neurotransmitter-enzyme system with multiple clinical applications" Prog Neurobiol.184:101722. doi: 10.1016/j.pneurobio.2019.101722.