Fycompa (perampanel) is an approved treatment for epilepsy when used combination with other drugs, but its use is associated with significant side effects. Now, a study explains exactly how this drug works, potentially paving the way to designing treatments that are equally or more effective and with a safer profile.
The study, “Structural Bases Of Noncompetitive Inhibition Of AMPA Subtype Ionotropic Glutamate Receptors By Antiepileptic Drugs,” published in the journal Neuron, was conducted by researchers at Columbia University Medical Center (CUMC).
Several proteins contribute to the propagation of electrical signals in the brain, which are the base for the communication among neurons. But in epileptic seizures, these signals are sent out in dysfunctional ways due to the abnormal workings of those proteins. AMPA receptors are a group of proteins that play a crucial role in neuronal signaling, and highly linked to epilepsy when they work poorly or wrongly.
For this reason, a number of treatments aim to inhibit the activity of these proteins. Because the proper functioning of AMPA receptors is so important for the brain, however, such therapies need to be considered with caution to avoid severe side effects, such as increased risk of neuropsychiatric events, irritability, aggression, anger, anxiety or paranoia. To date, Fycompa is the only drug that inhibits AMPA receptors approved by the U.S. Food and Drug Administration (FDA).
“The problem is that AMPA receptors are heavily involved in the central nervous system, so if you inhibit their function, you cause an array of unwanted effects,” Alexander Sobolevsky, PhD, and the study’s lead author, said in a news release. “If we hope to design better drugs for epilepsy, we need to learn more about the structure and function of these receptors.”
To understand exactly how Fycompa and other two inhibitors bind to the AMPA receptors and exert their anti-epileptic effect, the team used crystallography, a technique that allows the purification of proteins and the analysis of their structure. It allowed the researchers to look at the structure of AMPA receptors when Fycompa was bound to them, and identify exactly where the drug binds. According to the team, Fycompa wedges into the receptors, preventing them from being activated and stopping them from sending electrical signals among neurons.
Now that the mechanism of action of Fycompa and other inhibitors of the AMPA receptors is known, the team believes that it is now easier to develop medications that specifically target these proteins with a safer and more effective profile than currently exists.