Glycine transport inhibitors as potential antipsychotic drugs

Current antipsychotic drugs are only partially effective in treating schizophrenia and there is a clear need to develop better therapies. An alternative approach to develop new antipsychotics has come from the NMDA receptor hypofunction model for schizophrenia. It has been hypothesised that stimulation of NMDA receptors with glycine site agonists may be therapeutic, and a number of clinical trials of glycine together with standard antipsychotic drugs have been recently been conducted. Modest improvements in negative symptoms have been reported in some studies but a potentially more effective treatment is to use inhibitors of the GLYT1 subtype of glycine transporters. Expression of GLYT1 within the brain correlates with NMDA receptor expression patterns and it has been suggested that GLYT1 may regulate synaptic glycine concentrations. With the development of selective and potent non-transported inhibitors of GLYT1 it should be possible to elevate synaptic glycine concentrations more effectively and thereby to increase NMDA receptor activity. Recent in vitro studies demonstrate that the glycine transport inhibitor, N[3-(4-fluorophenyl)-3-(4'-phenylphenoxy)] propylsarcosine, enhances NMDA receptor activity and the use of this class of compounds in clinical studies is eagerly awaited.