title: Sodium channel inhibitor drug discovery using automated high throughput electrophysiology platforms.
abstract: Voltage dependent sodium channels are widely recognized as valuable targets for the development of therapeutic interventions for neuroexcitatory disorders such as epilepsy and pain as well as cardiac arrhythmias. An ongoing challenge for sodium channel drug discovery is the ability to readily evaluate state dependent interactions, which are known to underlie inhibition by many clinically used local anesthetic, antiepileptic and antiarrhythmic sodium channel blockers. While patch-clamp electrophysiology is still considered the most effective way of measuring ion channel function and pharmacology, it does not have the throughput to be useful in early stages of drug discovery in which there is often a need to evaluate many thousands to hundreds of thousands of compounds. Fortunately over the past five years, there has been significant progress in developing much higher throughput electrophysiology platforms like the PatchXpress and IonWorks, which are now widely used in drug discovery. This review highlights the strengths and weaknesses of these two high throughput devices for use in sodium channel inhibitor drug discovery programs. Overall, the PatchXpress and IonWorks electrophysiology platforms have individual strengths that make them complementary to each other. Both platforms are capable of measuring state dependent modulation of sodium channels. IonWorks has the throughput to allow for effective screening of libraries of tens of thousands of compounds whereas the PatchXpress has more flexibility to provide quantitative voltage clamp, which is useful in structure activity evaluations for the hit-to-lead and lead optimization stages of sodium channel drug discovery.
authors.affiliation: Icagen Inc., Durham, North Carolina 27703, USA. ncastle@icagen.com
authors.forename: Neil
authors.initials: N
authors.lastname: Castle
authors.forename: David
authors.initials: D
authors.lastname: Printzenhoff
authors.forename: Shannon
authors.initials: S
authors.lastname: Zellmer
authors.forename: Brett
authors.initials: B
authors.lastname: Antonio
authors.forename: Alan
authors.initials: A
authors.lastname: Wickenden
authors.forename: Christopher
authors.initials: C
authors.lastname: Silvia
mesh_terms: D001331:Automation; D055808:Drug Discovery / Q000379:methods*; D004594:Electrophysiology / Q000295:instrumentation* / Q000379:methods; D006801:Humans; D026941:Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: D026941:Sodium Channel Blockers