Molecular pharmacology of selective NaV1.6 and dual NaV1.6 and NaV1.2 channel inhibitors that suppress excitatory neuronal activity ex vivo

Goodchild, S. J.; Shuart, N. G.; Williams, A. D.; Ye, W.; Parrish, R. R.; Soriano, M.; Thouta, S.; Mezeyova, J.; Waldbrook, M.; Dean, R. A.; Focken, T.; Ghovanloo, M.-R.; Ruben, P. C.; Scott, F.; Cohen, C. J.; Empfield, J. R.; Johnson, J.

doi:10.1101/2023.08.03.551643

bioRxiv · 10.1101/2023.08.03.551643

Molecular pharmacology of selective NaV1.6 and dual NaV1.6 and NaV1.2 channel inhibitors that suppress excitatory neuronal activity ex vivo

Goodchild, S. J.·Shuart, N. G.·Williams, A. D.·Ye, W.·Parrish, R. R.·Soriano, M.·Thouta, S.·Mezeyova, J.·Waldbrook, M.·Dean, R. A.·Focken, T.·Ghovanloo, M.-R.·Ruben, P. C.·Scott, F.·Cohen, C. J.·Empfield, J. R.·Johnson, J.

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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 NaV 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 NaV1.6 and NaV1.2 channels in excitatory pyramidal neurons and possess a molecular selectivity of >100 fold against NaV1.1 channels that are dominant in inhibitory cells. This profile will enable pharmacological dissection of the physiological roles of NaV1.2 and NaV1.6 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 O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/551643v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@70750corg.highwire.dtl.DTLVardef@114756aorg.highwire.dtl.DTLVardef@289009org.highwire.dtl.DTLVardef@1086e23_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Goodchild, S. J., Shuart, N. G., Williams, A. D., Ye, W., Parrish, R. R., Soriano, M., Thouta, S., Mezeyova, J., Waldbrook, M., Dean, R. A., Focken, T., Ghovanloo, M.-R., Ruben, P. C., Scott, F., Cohen, C. J., Empfield, J. R., Johnson, J.. 2023-08-05. Molecular pharmacology of selective NaV1.6 and dual NaV1.6 and NaV1.2 channel inhibitors that suppress excitatory neuronal activity ex vivo. https://doi.org/10.1101/2023.08.03.551643

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