Current epilepsy treatment is not effective for all individuals. A new molecular investigation into the structure of new drug targets promises to help develop safer, more effective medicines for people with seizure disorders.
Epilepsy is a condition characterized by repeated seizures – sudden bursts of intense electrical activity in the brain.
An estimated 1.8 percent of adults have epilepsy; that equates to around 4.3. million Americans.
However, more often than not, the exact cause cannot be pinned down.
Currently, drug treatment for epilepsy is not effective for all people; in fact, the most common anti-epilepsy drugs do not work for almost 1 in 3 individuals with seizure disorders.
The search for better epilepsy medication is ongoing, and fresh hope has been found in a new set of pharmaceuticals: drugs that inhibit AMPA receptors.
A new approach to anti-epileptics
AMPA receptors are activated by glutamate, the brain’s primary excitatory neurotransmitter. These channels are involved in fast synaptic transmission in the CNS.
Although epilepsy is still not fully understood, glutamatergic neurons are thought to play a role in seizures, making any drug that blocks AMPA receptors a potential target for treatment.
AMPA receptors are the most numerous receptors in the CNS and are situated in many parts of the brain. So far, only one AMPA inhibitor drug is FDA-approved – perampanel.
Perampanel is effective, but the side effects are so troublesome that it has found only limited clinical use. Side effects can include dizziness, sleepiness, irritability, anxiety,stomach upset and nausea, problems with balance and coordination, vertigo, weight gain, and blurry vision.
Because perampanel is effective in reducing seizures, researchers are keen to improve the drug and minimize its side effects. To make these improvements, it is important to get a deeper understanding of the AMPA receptor.
A team from Columbia University Medical Center in New York, led by Prof. Alexander I. Sobolevsky, set out to investigate this mechanism on a molecular level. Their results are published this week in the journal Neuron.
“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. If we hope to design better drugs for epilepsy, we need to learn more about the structure and function of these receptors.”
Alexander I. Sobolevsky, professor of biochemistry and molecular biophysics
The team utilized a technique called crystallography to investigate how perampanel and other molecules interact with AMPA receptors. The team used rat AMPA receptors as they are virtually identical to the human version.
Prof. Sobolevsky was able to pinpoint the exact region that perampanel uses to interact with AMPA receptors. The data showed that the perampanel molecules “wedged themselves” into the receptor, preventing the channel from opening.
Once the AMPA receptor is closed, ions are prevented from passing into the cell, and the electrical signal is never triggered.
This is known as noncompetitive inhibition: a molecule binds to a part of the receptor other than the active site where molecules normally bind. In this way, it can change the receptor shape and prevent or hinder other molecules from attaching to the active site as they normally would.
Understanding molecular interactions at AMPA receptors
Additionally, the team found that perampanel binds easiest to the receptors when they do not already have a glutamate molecule attached to the active site. Medical News Todayasked Prof. Sobolevsky if he had any future studies planned. He said:
“We would like to understand the mechanism of noncompetitive inhibition in more detail. We solved structures of AMPA receptor with anti-epileptic drugs in the closed (inactive) state of the receptor. These drugs prefer to bind this state. The question is, why they don’t like binding other states of the receptor.”
There is clearly much more to learn about these interactions. Prof. Sobolevsky told MNTthat he would like to continue investigating other molecules that work at these sites, and he said: “The next logical step would be to collaborate with chemists and people who study animal models of diseases related to excitatory neurotransmission (including epilepsy), to design and test new drug candidates.”
Initially, the interaction sites of perampanel came as a surprise to the research team. As they considered their findings, however, it began to make sense, as Prof. Sobolevsky toldMNT:
“This is a beautiful example of how structural biology can give an insight into a complicated mechanism simply by providing a molecular view. This is when people say ‘you need to see it to understand it!'”
In the future, the team hopes that these findings will help drug designers develop AMPA receptor drugs that are more selective, more effective, and with reduced side effects.
Written by Tim Newman