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New epilepsy drugs work by jamming brain receptor

Date:
September 8, 2016
Source:
Columbia University Medical Center
Summary:
Researchers have discovered how a new epilepsy drug works, which may lead the way to even more effective and safer medications. Currently, the most commonly used anti-epilepsy drugs are ineffective for about 30 percent of people with seizure disorders.
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AMPA receptor (blue) is inactivated by antiepileptic drug Perampanel (yellow), which is wedged into binding sites on the upper edge of the cell membrane (gray and red).
Credit: Laboratory of Alexander Sobolevsky, PhD/Columbia University Medical Center

Columbia University Medical Center (CUMC) researchers have discovered how a new epilepsy drug works, which may lead the way to even more effective and safer medications.

The findings were published in Neuron.

The most commonly used anti-epilepsy drugs are ineffective for about 30 percent of people with seizure disorders.

A new direction in the treatment of epilepsy is aimed at inhibiting AMPA receptors, which help transmit electrical signals in the brain and play a key role in propagating seizures. Currently, perampanel is the only FDA-approved drug that targets AMPA receptors. But because perampanel is associated with significant side effects, its clinical use has been limited.

"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," said study leader Alexander I. Sobolevsky, PhD, professor of biochemistry and molecular biophysics at CUMC. "If we hope to design better drugs for epilepsy, we need to learn more about the structure and function of these receptors."

In this study, Dr. Sobolevsky employed a technique called crystallography to determine how perampanel and two other inhibitors interact with the AMPA receptors to stop transmission of electrical signals. The study was conducted using rat AMPA receptors, which are almost identical to human receptors.

In the new study, the researchers were able to pinpoint exactly where the drugs bind to AMPA receptors.

"Our data suggest that the inhibitors wedge themselves into the AMPA receptor, which prevents the opening of a channel within the receptor," said Dr. Sobolevsky. When that channel is closed, ions cannot pass into the cell to trigger an electrical signal.

According to the researchers, these findings may allow drug makers to develop medications that are highly selective for the AMPA receptors, which could be safer and more effective than currently available anti-epilepsy drugs.


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Materials provided by Columbia University Medical Center. Note: Content may be edited for style and length.


Journal Reference:

  1. Alexander I. Sobolevsky et al. Structural Bases of Noncompetitive Inhibition of AMPA-Subtype Ionotropic Glutamate Receptors by Antiepileptic Drugs. Neuron, September 2016 DOI: 10.1016/j.neuron.2016.08.012

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Columbia University Medical Center. "New epilepsy drugs work by jamming brain receptor." ScienceDaily. ScienceDaily, 8 September 2016. <www.sciencedaily.com/releases/2016/09/160908131230.htm>.
Columbia University Medical Center. (2016, September 8). New epilepsy drugs work by jamming brain receptor. ScienceDaily. Retrieved May 26, 2017 from www.sciencedaily.com/releases/2016/09/160908131230.htm
Columbia University Medical Center. "New epilepsy drugs work by jamming brain receptor." ScienceDaily. www.sciencedaily.com/releases/2016/09/160908131230.htm (accessed May 26, 2017).

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