N-Acetylaspartylglutamate (NAAG) is the third most prevalent
neurotransmitter in the mammalian nervous system, yet its therapeutic potential is only now being fully recognized. Drugs that inhibit the inactivation of NAAG by
glutamate carboxypeptidase II (GCPII) increase its extracellular concentration and its activation of its receptor,
mGluR3. These drugs warrant attention, as they are effective in animal models of several clinical disorders including
stroke,
traumatic brain injury and
schizophrenia. In inflammatory and
neuropathic pain studies, GCPII inhibitors moderated both the primary and secondary
pain responses when given systemically, locally or in brain regions associated with the pain perception pathway. The finding that GCPII inhibition also moderated the motor and cognitive effects of
ethanol intoxication led to the discovery of their procognitive efficacy in long-term memory tests in control mice and in short-term memory in a mouse model of
Alzheimer's disease. NAAG and GCPII inhibitors respectively reduce
cocaine self-administration and the rewarding effects of a synthetic stimulant. Most recently, GCPII inhibition also has been reported to be efficacious in a model of
inflammatory bowel disease. GCPII was first discovered as a
protein expressed by and released from metastatic prostate cells where it is known as prostate specific membrane
antigen (PSMA). GCPII inhibitors with high affinity for this
protein have been developed as prostate imaging and radiochemical
therapies for
prostate cancer. Taken together, these data militate in favor of the development and application of GCPII inhibitors in more advanced preclinical research as a prelude to clinical trials.