Ion channels represent an important class of druggable targets; however, it is generally appreciated in the field that ion-channel targeted drug discovery has been hampered by the unavailability of high-throughput platforms that use electrophysiological techniques for the characterization of compound activity. To address this bottleneck, in the past 5 years, several companies have developed and introduced automated platforms for performing electrophysiological studies.
This recent explosion includes different approaches taken to carry out multi-channel planar-array based patch-clamp recordings of mammalian cells, resulting in the commercialization of four systems — IonWorks, PatchXpress, Patchliner and CytoPatch. Complementary to these technologies has been the development of lower capacity systems that fully automate conventional manual patch-clamp recordings including the Flyscreen, AutoPatch and RoboPatch for mammalian cells, and the Robocyte and OpusXpress 6000A for Xenopus oocytes.
Despite the sophisticated technologies that are now available, automating patch-clamp electrophysiology often presents underestimated challenges regarding reproducibility with the cells being used; this needs to be fully appreciated when embarking on the implementation of any of these approaches.
The need to assess the potential of drug candidates to inhibit cardiac ion-channels, particularly hERG, has greatly contributed to the development of these technologies. Although higher throughput non-electrophysiological assays have a reasonable predictive potential, they have several limitations that might be technically or chemically limiting. Consequently, the desire to use electrophysiological assays early on to assess ion-channel liabilities has been one of the key drivers for implementation of automated electrophysiology.
Compound screening against molecularly isolated, heterologously expressed ion channels, will often identify drug candidates whose higher-order impact on networked neuronal systems are not necessarily inferable from their effects on individual conductances. Raising the throughput of pharmacological evaluation in such higher-order systems presents a distinct set of challenges. However, recent progress has been made in the development of automated systems for performing electrophysiogical studies in brain slices and other intact biological preparations.
The availability of these technologies has re-energized ion-channel targeted drug discovery by allowing the development of screening paradigms that were not feasible in the pre-automation era. In our opinion this holds much promise for the discovery and development of innovative new ion-channel targeted drugs. Tractability of ion channels as drug targets coupled with future advances in technology platforms and decreased cost of consumables are expected to support an even wider implementation of these automated systems.
Ion channels represent highly attractive targets for drug discovery and are implicated in a diverse range of disorders, in particular in the central nervous and cardiovascular systems. Moreover, assessment of cardiac ion-channel activity of new chemical entities is now an integral component of drug discovery programmes to assess potential for cardiovascular side effects. Despite their attractiveness as drug discovery targets ion channels remain an under-exploited target class, which is in large part due to the labour-intensive and low-throughput nature of patch-clamp electrophysiology. This Review provides an update on the current state-of-the-art for the various automated electrophysiology platforms that are now available and critically evaluates their impact in terms of ion-channel screening, lead optimization and the assessment of cardiac ion-channel safety liability.
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The authors thank A. Randall for comments on review.
The authors are all paid employess of Wyeth Research and receive company stock options as part of a compensation package.
- Faraday cage
An enclosure for blocking out external static electrical fields, made from a conducting material. It is named after the nineteenth-century physicist Michael Faraday.
The half maximal inhibitory concentration. This represents the concentration of an inhibitor that is required for 50% inhibition of a biological or molecular process.
- Z′ values
A measurement that takes into account the dynamic range of the assay (how far apart the positive controls are from the negative controls), as well as data variability (how much variation is seen in the measurements of positive and negative controls).
- Fluorescence-activated cell sorter
(FACS). A machine that can rapidly separate cells in suspension on the basis of size and the colour of their fluorescence.
- ICH regulations
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The ICH works to bring together government regulators and drug industry representatives from the United States, the European Union and Japan to make the international drug regulatory process more efficient and uniform.
- Long-term potentiation
(LTP). The prolonged strengthening of synaptic communication, which is induced by high-frequency patterned input and is thought to be involved in learning and memory formation.
- Long-term depression
(LTD). An enduring weakening of synaptic strength that is thought to interact with long-term potentiation (LTP) in the cellular mechanisms of learning and memory in structures such as the hippocampus and cerebellum. Unlike LTP, which is produced by brief high-frequency stimulation, LTD can be produced by long-term, low-frequency stimulation.
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Dunlop, J., Bowlby, M., Peri, R. et al. High-throughput electrophysiology: an emerging paradigm for ion-channel screening and physiology. Nat Rev Drug Discov 7, 358–368 (2008). https://doi.org/10.1038/nrd2552
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