Research ArticlesVolume 6, Spring 2012

Identification of Inhibitors of Phosphate-activated Glutaminase for the Pharmacotherapy of Schizophrenia

Cristina Sorrento1,

Stephen Rayport1,

Andra Mihali1,

Genevieve Kaunitz1,

Shreya Subramani1,

Joanne MacDonald2,

Francine Katz2

1 Department of Psychiatry, Columbia University, New York, NY 10032 & Department of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032,
2 Department of Medicine, Columbia University, New York, NY 10032

Abstract

In the brain, phosphate-activated glutaminase catalyzes the recycling of glutamine back to glutamate for excitatory neurotransmission. In mice, genetic knockdown of phosphate-activated glutaminase has been shown to confer resilience to schizophrenia-like symptoms, suggesting that inhibition of glutaminase may have therapeutic potential for the pharmacotherapy of schizophrenia. As there are no known neuroactive inhibitors of glutaminase, i.e. inhibitors that get into the brain, high-throughput screening of a library of 58,000 neuroative compounds was conducted using a fluorescence-based assay; this screen identified 320 potential glutaminase inhibitors. A secondary screen was carried out to access specificity; this yielded 10 hits. Using a kinetic analysis, two leads with low micromolar activity were found.