Schizophrenia is a highly debilitating mental disorder which afflicts approximately 1% of the global population.
Cognitive and negative deficits account for the lifelong disability associated with schizophrenia, whose symptoms
are not effectively addressed by current treatments. New medicines are needed to treat these aspects of the disease. Neurodevelopmental,
neuropathological, genetic, and behavioral pharmacological data indicate that schizophrenia stems from
a dysfunction of glutamate synaptic transmission, particularly in frontal cortical networks. A number of novel pre- and
postsynaptic mechanisms affecting glutamatergic synaptic transmission have emerged as viable targets for schizophrenia.
While developing orthosteric glutamatergic agents for these targets has proven extremely difficult, targeting allosteric
sites of these targets has emerged as a promising alternative. From a medicinal chemistry perspective, allosteric sites provide
an opportunity of finding agents with better drug-like properties and greater target specificity. Furthermore, allosteric
modulators are better suited to maintaining the highly precise temporal and spatial aspects of glutamatergic synaptic
transmission. Herein, we review neuropathological and genomic/genetic evidence underscoring the importance of glutamate
synaptic dysfunction in the etiology of schizophrenia and make a case for allosteric targets for therapeutic intervention.
We review progress in identifying allosteric modulators of AMPA receptors, NMDA receptors, and metabotropic
glutamate receptors, all with the aim of restoring physiological glutamatergic synaptic transmission. Challenges remain
given the complexity of schizophrenia and the difficulty in studying cognition in animals and humans. Nonetheless, important
compounds have emerged from these efforts and promising preclinical and variable clinical validation has been
Keywords: Allosterism, AMPA, glycine, glutamate, NAMS, NMDA, PAMS, schizophrenia
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