Molecular pharmacology of selective Na v 1.6 and dual Na v 1.6 and Na v 1.2 channel inhibitors that suppress excitatory neuronal activity ex vivo

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Abstract Sodium channel inhibitors are used to treat neurological disorders of hyperexcitability. However, all currently available sodium channel targeting anti-seizure medications are non-selective among the Na V isoforms which potentially limits efficacy and therapeutic safety margins. XPC-7724 and XPC-5462 represent a new class of small molecule compounds. These compounds target inhibition of the Na V 1.6 and Na V 1.2 channels in excitatory pyramidal neurons and possess a molecular selectivity of >100 fold against Na V 1.1 channels that are dominant in inhibitory cells. This profile will enable pharmacological dissection of the physiological roles of Na V 1.2 and Na V 1.6 and help to define the role of each channel in disease states. These compounds bind to and stabilize the inactivated-state of the channels, demonstrate higher potency with longer residency times, and slower off-rates than carbamazepine and phenytoin. These compounds possess cellular selectivity ex vivo in inhibiting action potential firing in cortical excitatory pyramidal neurons, whilst sparing fast spiking inhibitory interneurons. XPC-5462 also suppresses epileptiform activity in an ex vivo brain slice seizure model. This class of compounds provides a unique approach for treating neuronal excitability disorders by selectively down-regulating excitatory circuits. Graphical Abstract

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