Validation of a Medium-Throughput Electrophysiological Assay for KCNQ2/3 Channel Enhancers Using IonWorks HT

Jow, Flora; Shen, Ru; Chanda, Pranab K.; Tseng, Eugene; Zhang, Howard; Kennedy, Jeffrey D.; Dunlop, John; Bowlby, Mark R.

doi:10.1177/1087057107307448

Cited by 12 publications

(3 citation statements)

References 41 publications

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“…However, perhaps the biggest impact on ion channel drug discovery in recent years has been the development of higher throughput electrophysiological platforms. These range from the medium throughput systems like the high fidelity PatchXpress (Molecular Devices)252, Qpatch (Sophion)253,254 or PatchLiner (Nanion)255, which can test up to a 100 compounds per day to higher throughput platforms like IonWorks HT and Quattro (Molecular Devices)256,257 and more recently Qpatch HTX (press release from Sophion) that can test thousands of compounds per day. While not truly high throughput, when used in conjunction with other screening technologies, these new electrophysiology platforms have allowed for a higher fidelity and a more direct approach to K V channel drug discovery.…”

Section: Pharmacological Strategies For Modulation Of Kvchannel Functionmentioning

confidence: 99%

Voltage-gated potassium channels as therapeutic targets

Wulff

Castle²,

Pardo

2009

Nat Rev Drug Discov

673

567

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The human genome contains 40 voltage-gated potassium channels (K V ) which are involved in diverse physiological processes ranging from repolarization of neuronal or cardiac action potentials, over regulating calcium signaling and cell volume, to driving cellular proliferation and migration. K V channels offer tremendous opportunities for the development of new drugs for cancer, autoimmune diseases and metabolic, neurological and cardiovascular disorders. This review first discusses pharmacological strategies for targeting K V channels with venom peptides, antibodies and small molecules and then highlights recent progress in the preclinical and clinical development of drugs targeting K V 1.x, K V 7.x (KCNQ), K V 10.1 (EAG1) and K V 11.1 (hERG) channels.

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Section: Pharmacological Strategies For Modulation Of Kvchannel Functionmentioning

confidence: 99%

Voltage-gated potassium channels as therapeutic targets

Wulff

Castle²,

Pardo

2009

Nat Rev Drug Discov

673

567

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“…The compound SCR2682 was first synthesized by Shanghai Simcere Pharmaceuticals and identified as a potent Kv7.2 channel opener with an EC 50 of 0.26 mM among its derivatives using an atomic absorption Rb + efflux assay as previously described (36,37). The chemical structure of representative SCR2682 is depicted in Fig.…”

Section: Resultsmentioning

confidence: 99%

Electrophysiological and pharmacological characterization of a novel and potent neuronal Kv7 channel opener SCR2682 for antiepilepsy

et al. 2019

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Voltage‐gated Kv7/KCNQ/M potassium channels play an essential role in the control of membrane potential and neuronal excitability. Activation of the neuronal Kv7/KCNQ/M‐current represents an attractive therapeutic strategy for treatment of hyperexcitability‐related neuropsychiatric disorders such as epilepsy, pain, and depression, which is an unmet medical need. In this study, we synthesized and characterized a novel compound, N‐(4‐(2‐bromo‐6,7‐dihydrothieno[3,2‐c]pyridin‐5(4H)‐yl)‐2,6‐dimethylphenyl)‐3,3‐dimethylbutanamide (SCR2682) 2,6‐dimethyl‐4‐(piperidin‐yl) phenyl)‐amide derivative, that exhibits selective and potent activation of neuronal Kv7/KCNQ/M‐channels. Whole‐cell patch‐clamp recordings of human embryonic kidney 293 cells expressing Kv7.2/Kv7.3 channels show that SCR2682 selectively activates the channel current in a dose‐dependent manner with an EC50 of 9.8 ± 0.4 nM, which is ∼100‐fold more potent than a U.S. Food and Drug Administration–approved antiepileptic drug (retigabine) for treatment of partial epilepsy. SCR2682 shifts voltage‐dependent activation of the Kv7.2/7.3 current toward more negative membrane potential, to about −37 mV (V1/2). SCR2682 also activates the native M‐current in rat hippocampal or cortical neurons, causing marked hyperpolarization and potent inhibition of neuronal firings. Mechanistically, mutating the tryptophan residue 236 located at the fifth transmembrane segment of Kv7.2 abolishes the chemical activation of the channel by SCR2682. Furthermore, intraperitoneal or intragastric administration of SCR2682 results in a dose‐dependent inhibition of seizures by maximal electroshock. Taken together, our findings demonstrate that a novel small molecule, SCR2682, selectively and potently activates neuronal Kv7 channels and reverses epileptic seizures in rodents. Thus, SCR2682 may warrant further evaluation for clinical development of antiepileptic therapy.—Zhang, F., Liu, Y., Tang, F., Liang, B., Chen, H., Zhang, H., Wang, K. Electrophysiological and pharmacological characterization of a novel and potent neuronal Kv7 channel opener SCR2682 for antiepilepsy. FASEB J. 33, 9154–9166 (2019). http://www.fasebj.org

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“…The results are consistent with our unpublished data and previous reports using conventional patch clamp. 13,15,20 …”

Section: Effects Of Retigabine and Known Kcnq Openers And Blockers Onmentioning

confidence: 98%

Development and Validation of a Medium-Throughput Electrophysiological Assay for KCNQ2/3 Channel Openers Using QPatch HT

Zhang

Surowy

et al. 2013

ASSAY and Drug Development Technologies

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The KCNQ2/3 channel has emerged as a drug target for a number of neurological disorders including pain and epilepsy. Known KCNQ2/3 openers have effects on two distinct biophysical properties of the channel:(1) a hyperpolarizing shift in the voltage dependence of channel activation (V 1/2 ), and (2) an increase in channel open probability or peak wholecell current. The current high-throughput screening assays for KCNQ2/3 openers measure changes of channel activity at sub-peak conductances and the output measure is a combination of effects on V 1/2 shift and peak current. Here, we describe a medium-throughput electrophysiological assay for screening KCNQ2/3 openers using the QPatch HT platform. We employed a double-pulse protocol that measures the shift in V 1/2 and the change in current amplitude at peak conductance voltage. Retigabine along with novel KCNQ2/3 openers were evaluated in this assay. Three classes of KCNQ2/3 openers were identified based on the hyperpolarizing shift in V 1/2 and the change in peak current. All three classes of compounds caused a hyperpolarizing shift in V 1/2 , but they were differentiated by their respective effects on peak current amplitude (increase, decrease, or only modestly affecting peak current amplitude). KCNQ2/3 blockers were also identified with this assay. These compounds blocked currents without affecting voltage-dependent activation. In summary, we have developed a medium-throughput assay that can reliably detect changes in the biophysical properties of the KCNQ2/3 channel, V 1/2, and peak current amplitude, and therefore may serve as a reliable assay to evaluate KCNQ2/3 openers and blockers.

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Validation of a Medium-Throughput Electrophysiological Assay for KCNQ2/3 Channel Enhancers Using IonWorks HT

Cited by 12 publications

References 41 publications

Voltage-gated potassium channels as therapeutic targets

Voltage-gated potassium channels as therapeutic targets

Electrophysiological and pharmacological characterization of a novel and potent neuronal Kv7 channel opener SCR2682 for antiepilepsy

Development and Validation of a Medium-Throughput Electrophysiological Assay for KCNQ2/3 Channel Openers Using QPatch HT

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