AGY's cognition/schizophrenia program is focused on modulating NMDA receptor (NMDAR) function through inhibition of interacting protein tyrosine phosphatases. A wealth of research has demonstrated that NMDAR dysfunction can contribute to numerous neurological disorders including Alzheimer's disease and schizophrenia. AGY is pursuing an alternative strategy to current approaches, which provides specificity of action and opens a new path for treatment of mental disorders.

The majority of excitatory synaptic transmission in the CNS is mediated by the neurotransmitter glutamate acting on postsynaptic receptors. The NMDAR is unique among glutamatergic receptors in that it requires both membrane depolarization and agonist binding for its activation. Many studies have established the role of NMDARs in experimental paradigms for memory formation including long term potentiation (LTP) and long term depression (LTD). Transgenic models have also demonstrated that memory can be enhanced by overexpression of NMDA receptors.

Hypofunction of NMDARs contributes to the negative symptoms of schizophrenia and possibly cognitive impairments in Alzheimer's disease. Clinical trials of NMDAR co-agonists such as D-cycloserine in schizophrenia patients support the approach of enhancement of NMDAR function as a potential treatment. Genetic, genomic and SNP studies in schizophrenia have identified several proteins involved in glutamatergic neurotransmission.

Given the central role of NMDARs in both normal synaptic functioning and pathological conditions, the enhancement, or restoration, of NMDAR function is a promising new approach for treatment of cognitive and mental disorders.

To achieve this aim, AGY has identified proteins that interact with NMDARs to modulate receptor function. These include the tyrosine phosphatases AGY-111 and AGY-112 that regulate the NMDAR's phosphorylation state. Phosphorylation is a well characterized mechanism for modulating the efficacy of conduction through the NMDAR channel and for the delivery of receptors to the synapse. By modulation of phosphorylation processes, we are taking advantage of the brain's endogenous control mechanisms to fine tune receptor function, providing a greater potential to avoid side effects than the direct agonist or antagonist approaches.

AGY has identified inhibitors of these tyrosine phosphatases that potentiate NMDAR function and may lead to novel therapeutics for conditions such as cognitive deficits and schizophrenia for which a hypofunction of the NMDAR activity has been suggested as an important pathological mechanism.

AGY has established a broad intellectual property position for the most valuable targets and lead compounds. In addition, the company established an intellectual property portfolio protecting its key technologies, including molecular cloning, bioinformatics for pathways, as well as the use of RNA interference (RNAi) in neurons and glial cells.
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