Clinically utilized
antipsychotic agents share as a common mechanism the ability to antagonize
dopamine D2 receptors and it is widely assumed that this activity contributes to their efficacy against the positive symptoms of
schizophrenia. The efficacy of currently marketed
antipsychotic agents on the negative and
cognitive symptoms of this disease, however, is not optimal. One alternate hypothesis to the "
dopamine hypothesis" of
schizophrenia derives from the observation that antagonists of
NMDA receptor activity better mimic the symptomatology of
schizophrenia in its entirety than do
dopamine agonists. Findings from this line of research have led to the
NMDA receptor hypofunction (or
glutamate dysfunction) hypothesis of
schizophrenia, which complements existing research implicating
dopamine dysfunction in the disease. According to the
NMDA receptor hypofunction hypothesis, any treatment that enhances
NMDA receptor activity may prove useful for the treatment of the complex symptoms that define
schizophrenia. This idea is now supported by numerous clinical studies that have reported an efficacious response following treatment with activators of the
NMDA receptor co-agonist glycineB site. One area of study, aimed at potentiating the
NMDA receptor via activation of the glycineB site is small molecule blockade of the
glycine reuptake transporter type 1 (GlyT1). Broadly, these efforts have focused on derivatives of the substrate inhibitor,
sarcosine, and non-
sarcosine based GlyT1 inhibitors. Accordingly, the following review discusses the development of both
sarcosine and non-
sarcosine based GlyT1 inhibitors and their current status as putative treatments for
schizophrenia and other disorders associated with
NMDA receptor hypoactivity.