How could perampanel, a potent AMPAergic antagonist, inhibit seizures but largely spare normal neurotransmission?

AMPAR activation constitutes two sequential processes, namely the association (glutamate binding) and the transformation (protein conformational change) steps. Perampanel slows transformation, resulting in glutamate-dependent bidirectional effects. In seizures and high ambient glutamate, the association steps are so fast that the transformation steps are relatively rate-limiting in AMPAR activation. However, a synchronisation effect of perampanel may emerge in low and variable glutamate (by shifting the rate-limiting role to the slowed and more uniform transformation steps). Perampanel can therefore selectively inhibit ictal discharges, but may also contribute to inadvertent seizure aggravation or psychiatric events with the potential synchronisation effect. The latter can be managed by deliberate and delicate up-or-down titration of the perampanel clinical dosage.