Compound 1028 is a potent, brain-permeable small molecule that targets FGF14 R117 with binding KD of 293 nM (SPR), selectively modulates FGF14/Nav1.6 complex assembly and depolarizes the voltage-dependence of Nav1.6 channel inactivation.
Compound 1028 shows no detectable binding to the Nav1.6 CTD, but modulates the intramolecular interaction between the III-IV linker and C-terminal domain of the Nav1.6 channel.
Compound 1028 (1 uM) caused a depolarizing shift in the voltage-dependence of steady-state inactivation of INa in HEK293 cells transiently transfected with Nav1.6WT and FGF14.
Compound 1028 shows no effect on the voltage-dependence of steady-state inactivation of INa in HEK293 cells expressing Nav1.1 and FGF14 or Nav1.2 and FGF14.
Compound 1028 enhances medium spiny neurons (MSN) excitability ex vivo and accumbal neuron firing rate in vivo in murine models, displays behavioral motivation preferentially during motivationally deficient conditions.