| Autor: |
Goodchild SJ; Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada., Shuart NG; Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada., Williams AD; Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada., Ye W; Neurocrine Biosciences, San Diego, California 92130, United States., Parrish RR; Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada., Soriano M; Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada., Thouta S; Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada., Mezeyova J; Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada., Waldbrook M; Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada., Dean R; Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada., Focken T; Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada., Ghovanloo MR; Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada.; Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.; Department of Neurology, Yale University, New Haven, Connecticut 06519, United States., Ruben PC; Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada., Scott F; Neurocrine Biosciences, San Diego, California 92130, United States., Cohen CJ; Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada., Empfield J; Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada., Johnson JP; Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada. |
| Abstrakt: |
Voltage-gated sodium channel (Na V ) 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 Na V -targeting antiseizure medications nonselectively inhibit the brain channels Na V 1.1, Na V 1.2, and Na V 1.6, 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 Na V -targeting compounds. These compounds specifically target inhibition of the Na V 1.6 and Na V 1.2 channels, which are abundantly expressed in excitatory pyramidal neurons. They have a > 100-fold molecular selectivity against Na V 1.1 channels, which are predominantly expressed in inhibitory neurons. Sparing Na V 1.1 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-Mg 2+ - or 4-AP-induced brain slice seizure models. The profiles of these compounds will facilitate pharmacological dissection of the physiological roles of Na V 1.2 and Na V 1.6 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. |
