NAAG peptidase inhibitors and their potential for diagnosis and therapy

Key Points Glutamate (Glu) is the most abundant excitatory transmitter in the central nervous system. However, excessive glutamatergic transmission can damage or kill neurons, and has therefore been implicated in a variety of neurological disorders. N -Acetyl- L -aspartyl- L -glutamate (NAAG), one of the three most prevalent neurotransmitters, acts as an agonist at group II metabotropic glutamate receptors with preference for metabotropic glutamate (mGlu 3 ) receptors on neurons and glia. Two extracellular enzymes, glutamate carboxypeptidase II and III (GCPII and III), hydrolyse NAAG to N -acetylaspartate (NAA) and glutamate following its release into the synaptic cleft. Inhibition of these NAAG peptidases (NPs) is thought to provide neuroprotection by increasing the intrasynaptic concentration of NAAG. NAAG decreases the release of glutamate by activation of presynaptic group II mGlu receptors and stimulates release of trophic factors from glia. Those actions of NAAG may provide neuroprotection in clinical conditions in which glutamate mediates and mGlu 3 receptor activation reduces pathology. Importantly, NP inhibitors do not seem to affect normal glutamate function. NP inhibition enhances a natural ongoing regulatory process rather than chronically activating or inhibiting receptors in a manner that is unrelated to ongoing chemical neurotransmission. NP represents an intriguing target for drug discovery aimed at unmet medical needs. Additionally, human GCPII has also been identified as prostate-specific membrane antigen (PSMA), a cell surface protein expressed in elevated levels by prostate cancer. Its X-ray crystal structure was recently reported. Studies using small-molecule-based NP inhibitors have confirmed their beneficial effects in animal models relevant to neurodegenerative diseases as well as cancer. NP inhibitors therefore have significant potential for use as both diagnostic and therapeutic agents. Specific applications include neuropathic and inflammatory pain, traumatic brain injury, ischemic stroke, schizophrenia, diabetic neuropathy, amyotrophic lateral sclerosis, drug addiction, as well as prostate cancer. Modulation of N -acetyl- L -aspartyl- L -glutamate peptidase activity with small-molecule inhibitors holds promise for a wide variety of diseases that involve glutamatergic transmission, and has implications for the diagnosis and therapy of cancer. This new class of compounds, of which at least one has entered clinical trials and prove