Epilepsy is broadly considered an imbalance between too MUCH excitatory signaling via the neurotransmitter, glutamate, and too LITTLE inhibitory tone via the neurotransmitter, GABA. GABA‑A receptors are the primary ionotropic channel mediating chloride ion influx and thus fast inhibitory neurotransmission.
GABA-A receptors are pentameric structures that include several subunits (α, β, γ, etc.). The α‑subunit is especially important because it influences:
- Where the GABA-A receptor is located in the brain
- How GABA-A receptors respond to various pharmacological compounds
- Whether activating GABA-A receptors causes calming, sedating, or anticonvulsant effects. Indeed, α1‑containing receptors are typically involved in sedating effects whereas α2, α3, and α5 are more typically associated with anxiolytic and anticonvulsant effects.
Benzodiazepines (e.g., diazepam) work broadly to stop seizures, but they also cause significant sedation. Benzodiazepines activate multiple subtypes of the GABA-A receptor subunits, including α1. This makes them less desirable for chronic use in people with epilepsy - who wants an excessively sleepy patient, even if the seizures are under control?
Our study characterized the in vivo therapeutic response profile of the novel GABA-A positive allosteric modulator, ENX-101. ENX-101 is a subunit selective GABA-A positive allosteric modulator (PAM). It acts primarily at GABAA receptors containing α2, α3, or α5 subunits. This study confirms that this compound is well-tolerated and demonstrates minimal sedating effects at anticonvulsant doses, warranting further in vivo preclinical study and potential clinical evaluation in people with focal onset seizures.
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