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

Abstract

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

Discovery of HN37 as a Potent and Chemically Stable Antiepileptic Drug Candidate

“…33,34 Recently, Zhang et al reported a novel potent neuronal Kv7 channel opener SCR2682 also containing two ortho methyl substituents. 35,36 Besides, compound XEN1101 (1OP-2198), one of a series of 4-(N-azacycloalkyl) anilides with two ortho methyl substituents, has progressed into Phase 2 clinical trial to treat focal epilepsy (ClinicalTrials.gov Identifier: NCT03796962). 37−39 Both RTG and flupirtine share a motif of arene orthodiamines with one acylated and another as an unsubstituted primary amine.…”

“…For example, Yang et al . developed a series of piperidine-based di-ortho-methyl-substituted butanamides using a hybridization drug design strategy. , Recently, Zhang et al reported a novel potent neuronal Kv7 channel opener SCR2682 also containing two ortho methyl substituents. , Besides, compound XEN1101 (1OP-2198), one of a series of 4-( N -azacycloalkyl) anilides with two ortho methyl substituents, has progressed into Phase 2 clinical trial to treat focal epilepsy (ClinicalTrials.gov Identifier: NCT03796962). − …”

Small‐molecule‐driven direct reprogramming of Müller cells into bipolar‐like cells

“…Additionally, the electrophysiological features of chemically induced neurons (CiNs), were investigated using the whole-cell patch-clamp technique, showing action potentials (APs) and inward currents (Figure S1E,F). 21 Overall, small-molecule-driven direct reprogramming could generate neuron-like cells with neuronal morphology and features from astrocytes.…”

Detrusor Smooth Muscle KV7 Channels: Emerging New Regulators of Urinary Bladder Function

“…They include (1) retigabine and flupirtine, both pan-specific activators of K V 7.2-K V 7.5 channels; (2) ICA-069673, a selective activator of K V 7.2/K V 7.3 channels; (3) ML213, a preferential activator of K V 7.2, K V 7.2/K V 7.3, and K V 7.4 channels; (4) XE991 and linopirdine, pan-selective inhibitors of K V 7.1-K V 7.5 channels ( Miceli et al, 2008 , 2018 ; Yu et al, 2010 , 2011 ; Amato et al, 2011 ; Barrese et al, 2018b ). More recently, the next generation of subtype-specific and selective modulators for K V 7.2/K V 7.3 and K V 7.4/K V 7.5 channels has been described ( Liu et al, 2019 ; Osuma et al, 2019 ; Zhang et al, 2019 ; Ostacolo et al, 2020 ). These compounds provide an excellent opportunity to determine the functions of K V 7 channels subtypes in DSM and elsewhere.…”