NMDA receptor antagonists Subject

Several lines of evidence have implicated NMDA receptor hypofunction in the pathophysiology of schizophrenia. The administration of certain, but not all, uncompetitive NMDA receptor antagonists exacerbates psychotic symptoms in schizophrenics and mimics schizophrenia in non-psychotic subjects (Coyle et al. 2003 Konradi and Heckers 2003). 

Glutamate was initially implicated in schizophrenia by studies of the behavioral effects of N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., PCP, ketamine), which produce psychotic symptoms and cognitive dysfunction in healthy subjects and exacerbate psychotic, negative, and cognitive symptoms in patients with schizophrenia. Studies show that acute administration of NMDA antagonists causes NMDA receptor dysfunction, resulting in decreased inhibition of subcortical dopamine neurons and consequent increased mesolimbic dopamine release. Chronic administration produces decreased release, or hypoactivity, of dopamine in the prefrontal cortex (Davis and Lieberman, 2000). 

Access to chiral 1-substituted tetrahydro-3-benzazepines by aysmmetric sysnthesis has been reported <2007EJ0462>. The synthesis began with o-phenylenediacetic acid and (R)-phenylglycinol, and proceeded via an acid catalyzed type a ring constmction to afford an intermediate oxazolobenzazepinone. This intermediate in turn was then subjected to lactam reduction followed by hydrogenolytic removal of the N-substituent to afford the chiral reduced 3-benzazepines, which were evaluated as NMDA receptor antagonists. 

This hypothesis is further supported by the similarities between the behavioral effects caused by the administration of N-methyl-o-aspartate (NMDA) receptor antagonists to human subjects and the clinical symptoms of schizophrenia. Moreover, clinical trials in which NMDA receptor activity was enhanced by agents acting at the glycine modulatory site have demonstrated decreases in negative symptoms and variable improvements in cognitive function. There are also data from postmortem studies suggesting alterations in... 

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