1 research outputs found
Molecular Pharmacology of Selective Na<sub>V</sub>1.6 and Dual Na<sub>V</sub>1.6/Na<sub>V</sub>1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo
Voltage-gated sodium channel (NaV) inhibitors
are used
to treat neurological disorders of hyperexcitability such as epilepsy.
These drugs act by attenuating neuronal action potential firing to
reduce excitability in the brain. However, all currently available
NaV-targeting antiseizure medications nonselectively inhibit
the brain channels NaV1.1, NaV1.2, and NaV1.6, which potentially limits the efficacy and therapeutic
safety margins of these drugs. Here, we report on XPC-7724 and XPC-5462,
which represent a new class of small molecule NaV-targeting
compounds. These compounds specifically target inhibition of the NaV1.6 and NaV1.2 channels, which are abundantly expressed
in excitatory pyramidal neurons. They have a > 100-fold molecular
selectivity against NaV1.1 channels, which are predominantly
expressed in inhibitory neurons. Sparing NaV1.1 preserves
the inhibitory activity in the brain. These compounds bind to and
stabilize the inactivated state of the channels thereby reducing the
activity of excitatory neurons. They have higher potency, with longer
residency times and slower off-rates, than the clinically used antiseizure
medications carbamazepine and phenytoin. The neuronal selectivity
of these compounds is demonstrated in brain slices by inhibition of
firing in cortical excitatory pyramidal neurons, without impacting
fast spiking inhibitory interneurons. XPC-5462 also suppresses epileptiform
activity in an ex vivo brain slice seizure model, whereas XPC-7224
does not, suggesting a possible requirement of Nav1.2 inhibition in
0-Mg2+- or 4-AP-induced brain slice seizure models. The
profiles of these compounds will facilitate pharmacological dissection
of the physiological roles of NaV1.2 and NaV1.6 in neurons and help define the role of specific channels in disease
states. This unique selectivity profile provides a new approach to
potentially treat disorders of neuronal hyperexcitability by selectively
downregulating excitatory circuits