The contribution of Na1.6 to the efficacy of voltage-gated sodium channel inhibitors in wild type and Na1.6 gain-of-function (GOF) mouse seizure control.

Background And Purpose: Inhibitors of voltage-gated sodium channels (Nas) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non-selective. We aimed to create novel, isoform selective inhibitors of Na channels as a means of informing the development of improved antiseizure drugs.

Experimental Approach: We created a series of compounds with diverse selectivity profiles enabling block of Na1.

Molecular Pharmacology of Selective Na1.6 and Dual Na1.6/Na1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo.

Voltage-gated sodium channel (Na) 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-targeting antiseizure medications nonselectively inhibit the brain channels Na1.

Expanding the genotype-phenotype spectrum in SCN8A-related disorders.

Background: SCN8A-related disorders are a group of variable conditions caused by pathogenic variations in SCN8A. Online Mendelian Inheritance in Man (OMIM) terms them as developmental and epileptic encephalopathy 13, benign familial infantile seizures 5 or cognitive impairment with or without cerebellar ataxia.

Methods: In this study, we describe clinical and genetic results on eight individuals from six families with SCN8A pathogenic variants identified via exome sequencing.

Expanding the genotype-phenotype spectrum in SCN8A-related disorders.

Background: -related disorders are a group of variable conditions caused by pathogenic variations in . Online Mendelian Inheritance in Man (OMIM) terms them as developmental and epileptic encephalopathy 13, benign familial infantile seizures 5 or cognitive impairment with or without cerebellar ataxia.

Methods: In this study, we describe clinical and genetic results on eight individuals from six families with pathogenic variants identified via exome sequencing.

Pharmacological determination of the fractional block of Nav channels required to impair neuronal excitability and seizures.

Voltage-gated sodium channels (Nav) are essential for the initiation and propagation of action potentials in neurons. Of the nine human channel subtypes, Nav1.1, Nav1.

NBI-921352, a first-in-class, Na1.6 selective, sodium channel inhibitor that prevents seizures in gain-of-function mice, and wild-type mice and rats.

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target Na1.6 channels. Such a molecule provides a precision-medicine approach to target -related epilepsy syndromes (-RES), where gain-of-function (GoF) mutations lead to excess Na1.

Identification of aryl sulfonamides as novel and potent inhibitors of Na1.5.

We describe the synthesis and biological evaluation of a series of novel aryl sulfonamides that exhibit potent inhibition of Na1.5. Unlike local anesthetics that are currently used for treatment of Long QT Syndrome 3 (LQT-3), the most potent compound (-)-6 in this series shows high selectivity over hERG and other cardiac ion channels and has a low brain to plasma ratio to minimize CNS side effects.

Discovery of Acyl-sulfonamide Na1.7 Inhibitors GDC-0276 and GDC-0310.

Na1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 () and GDC-0310 (), selective Na1.

Inhibitory effects of cannabidiol on voltage-dependent sodium currents.

contains many related compounds known as phytocannabinoids. The main psychoactive and nonpsychoactive compounds are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), respectively. Much of the evidence for clinical efficacy of CBD-mediated antiepileptic effects has been from case reports or smaller surveys.

T-type calcium channel blockers that attenuate thalamic burst firing and suppress absence seizures.

Absence seizures are a common seizure type in children with genetic generalized epilepsy and are characterized by a temporary loss of awareness, arrest of physical activity, and accompanying spike-and-wave discharges on an electroencephalogram. They arise from abnormal, hypersynchronous neuronal firing in brain thalamocortical circuits. Currently available therapeutic agents are only partially effective and act on multiple molecular targets, including γ-aminobutyric acid (GABA) transaminase, sodium channels, and calcium (Ca(2+)) channels.

Identification of sodium channel isoforms that mediate action potential firing in lamina I/II spinal cord neurons.

Background: Voltage-gated sodium channels play key roles in acute and chronic pain processing. The molecular, biophysical, and pharmacological properties of sodium channel currents have been extensively studied for peripheral nociceptors while the properties of sodium channel currents in dorsal horn spinal cord neurons remain incompletely understood. Thus far, investigations into the roles of sodium channel function in nociceptive signaling have primarily focused on recombinant channels or peripheral nociceptors.

A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain.

Voltage-gated ion channels are implicated in pain sensation and transmission signaling mechanisms within both peripheral nociceptors and the spinal cord. Genetic knockdown and knockout experiments have shown that specific channel isoforms, including Na(V)1.7 and Na(V)1.

A fluorescence-based high-throughput screening assay for the identification of T-type calcium channel blockers.

T-type voltage-gated Ca(2+) channels have been implicated in contributing to a broad variety of human disorders, including pain, epilepsy, sleep disturbances, cardiac arrhythmias, and certain types of cancer. However, potent and selective T-type Ca(2+) channel modulators are not yet available for clinical use. This may in part be due to their unique biophysical properties that have delayed the development of high-throughput screening (HTS) assays for identifying blockers.

Functional analysis of Ca3.2 T-type calcium channel mutations linked to childhood absence epilepsy.

Purpose: Childhood absence epilepsy (CAE) is an idiopathic form of seizure disorder that is believed to have a genetic basis.

Methods: We examined the biophysical consequences of seven mutations in the Ca(v)3.2 T-type calcium channel gene linked to CAE.

Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy.

Childhood absence epilepsy (CAE) is a type of generalized epilepsy observed in 2-10% of epileptic children. In a recent study by Chen et al. (Chen, Y.

Differential inhibition of T-type calcium channels by neuroleptics.

T-type calcium channels play critical roles in cellular excitability and have been implicated in the pathogenesis of a variety of neurological disorders including epilepsy. Although there have been reports that certain neuroleptics that primarily target D2 dopamine receptors and are used to treat psychoses may also interact with T-type Ca channels, there has been no systematic examination of this phenomenon. In the present paper we provide a detailed analysis of the effects of several widely used neuroleptic agents on a family of exogenously expressed neuronal T-type Ca channels (alpha1G, alpha1H, and alpha1I subtypes).