CERC-611 is being developed as an adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy.
AMPA receptors are glutamate-sensitive ion channels on postsynaptic membranes of excitatory synapses in the central nervous system and are largely responsible for mediating fast neurotransmission across synaptic gaps. AMPA receptor antagonists are known anticonvulsant agents and their ability to down-modulate excitatory neurotransmission is key to their antiepileptic therapeutic potential.
Transmembrane AMPA receptor regulatory proteins (TARPs) are a recently discovered family of proteins that have been found to associate with and modulate the activity of AMPA receptors. Several TARPs are fairly region-specific in the brain, leading to physiological differentiation of AMPA receptor activity. For example, TARPγ2 (stargazing)-dependent AMPA receptors are primarily localized in the cerebellum and cerebral cortex and TARPγ8-dependent AMPA receptors are localized primarily in the hippocampus, a region which is particularly relevant to seizure origination and/or propagation. It has been theorized that targeting individual TARPs may enable selective modulation of specific brain circuits without globally affecting synaptic transmission.
CERC-611 is the first molecule to selectively target and functionally block regionally-specific AMPA receptors after oral dosing. This selectivity was engineered into CERC-611 using structure-activity relationship information to achieve selective blockade of the AMPA receptor regulatory protein or TARP-γ8 while sparing AMPA receptors associated with TARP γ2. CERC-611 is the first molecule to selectively target TARP-γ8-containing AMPA receptors.