EPILEPSY drugs designed to target glutamatergic AMPA receptors have been revealed to act as ‘wedges’, preventing dysregulated transmission of electrical signals within the brain.
Epilepsy affects 1.8% of the adult population worldwide, yet no drug is available to effectively treat all individuals at present. As seizure disorders are extremely complicated, the exact cause and mechanisms of the condition differs between patients, making the challenge of drug discovery and design extremely difficult. It is estimated that one-third of patients are unable to find relief using conventional drugs already available on the market.
The search for novel seizure therapeutics has led researchers to investigate non-competitive AMPA receptor inhibitors. These receptors have a dominant role in the transmission of excitatory signals, the dysregulation of which is thought to contribute to epileptogenesis. Currently, perampanel is the only drug designed to inhibit transmission across glutamatergic neurons, approved for clinical use by the US Food and Drug Administration (FDA). Although able to dampen symptoms, perampanel is also a non-selective inhibitor, leading to side effects severe enough to affect quality of life, including vertigo, insomnia, and visual complications.
To investigate the structure of AMPA receptors and their interactions with drugs such as perampanel, Prof Alexander Sobolevsky, Columbia University Medical Center, New York City, New York, USA, and colleagues used crystallography to study rat AMPA-subtype GluA2 receptors, both with and without the addition of non-competitive inhibitors. Results confirmed that these drugs are able to bind and stabilise a domain separate to the active domain. However, it was discovered that a closed receptor state was maintained by a ‘wedging’ mechanism at the interface between the channel and ligand-binding domain, preventing signals from being triggered.
Prof Sobolevsky stated: “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!’” It is hoped that this discovery will aid drug designers by providing a detailed, selective mechanism to work towards. Results indicated that perampanel binds preferably to AMPA receptors already in the closed state, without glutamate bound to their active site. The team intends to research this aspect further using different drugs of a similar nature to investigate whether this may unlock the key to creating a drug without severe side effects.