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MDI-26478, the treatment candidate being developed by Cardiff University’s Medicines Discovery Institute, is a positive allosteric modulator of the AMPA receptor and is being investigated for its potential in treating schizophrenia.
The AMPA receptor is a type of glutamate receptor in the brain that is involved in excitatory neurotransmission. It plays a crucial role in synaptic plasticity, which is important for learning, memory, and overall brain function. Dysregulation of glutamate signaling, including abnormalities in AMPA receptor function, has been implicated in the pathophysiology of schizophrenia.
As a positive allosteric modulator, MDI-26478 enhances the function of the AMPA receptor by binding to a different site on the receptor and increasing its activity. By modulating the AMPA receptor, the drug aims to improve synaptic transmission and restore normal glutamate signaling in individuals with schizophrenia.
AMPA receptors play a critical role in glutamate transmission, which is the process by which glutamate, the primary excitatory neurotransmitter in the brain, carries signals between neurons. When glutamate is released from the presynaptic neuron, it binds to and activates various glutamate receptors, including the AMPA receptor.
Upon binding of glutamate, the AMPA receptor undergoes a conformational change that allows the influx of positively charged ions, predominantly sodium (Na+) ions, into the postsynaptic neuron. This influx of ions leads to depolarization of the postsynaptic neuron, generating an excitatory response.
The activation of AMPA receptors contributes to fast excitatory neurotransmission in the brain. It is essential for processes such as synaptic plasticity, which underlies learning and memory formation. The strength of synaptic connections can be modified through changes in the number and activity of AMPA receptors, a phenomenon known as synaptic plasticity.
AMPA receptors work in conjunction with other glutamate receptors, such as NMDA (N-methyl-D-aspartate) receptors, to mediate glutamate transmission. The combined activation of AMPA and NMDA receptors is crucial for various physiological processes, including the establishment and refinement of neural circuits during development, synaptic strengthening, and the maintenance of proper neuronal communication.
Abnormalities in AMPA receptor function or glutamate transmission can have profound effects on brain function and contribute to neurological and psychiatric disorders. Modulating AMPA receptor activity, such as through positive allosteric modulation, aims to restore or enhance glutamate transmission and address disruptions in neuronal communication associated with these conditions.