Treating NMDA Receptor Hypofunction

Glutamate Hypothesis and Treating NMDA Receptor Hypofunction

A new hypothesis has developed from the observations that blockade of the NMDA (N-methyl D-aspartate) glutamate receptor can precipitate schizophrenic-like symptoms in both normal humans and animal models of the disease. This hypothesis stipulates that reduced activation of the glutamatergic signaling pathways through the NMDA receptor is the underlying cause of the symptoms of schizophrenia. Glutamate, the main excitatory neurotransmitter in the CNS, is the primary ligand for the NMDA receptor, but this receptor also requires binding of glycine for activation.

Selective inhibition of GlyT-1 increases glycine levels in close proximity to the NMDA receptor. Increasing glycine levels in the synapse is anticipated to counteract the reduced function of the NMDA receptor; therefore, the activation of the downstream neurons in response to glutamate release will be normalized.

AMRI believes that inhibitors of GlyT-1 will provide a differentiated treatment for not only the positive, but also the negative and cognitive symptoms of schizophrenia without inducing the side-effects associated with the anti-psychotic medications on the market today. The positive phase II results of Roche’s compound (R1678) in improving the negative symptoms of schizophrenia and patient’s personal and social performance has stimulated further interest in the development of GlyT-1 inhibitors.

For more information, download the following posters pertaining to our GlyT-1 inhibitor program: