Development of an automated screen for Kv7.2 potassium channels and discovery of a new agonist chemotype

Hernández, Ciria C.; Tarfa, Rahilla A.; Limcaoco, Jose Miguel I.; Liu, Ruiting; Mondal, Pravat; Hill, Clare; Duncan, R. Keith; Tzounopoulos, Thanos; Stephenson, Corey R. J.; O’Meara, Matthew J.; Wipf, Peter

doi:10.1016/j.bmcl.2022.128841

Cited by 8 publications

(7 citation statements)

References 28 publications

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“…Blue triangles (▲) indicate residues that celecoxib interacts with (Du et al, 2011). Gold triangles (▲) indicate residues that ZK-21 interacts with (Hernandez et al, 2022) findings are taken together with our present results, they highlight a more complex picture than what is seen in other hK V 7 channels, namely, that compounds that interact with putative coupling residues in hK V 7.1 may either activate or inhibit the channel through a similar site. The relevance of this shared site is further illustrated by scrutinizing the structures of NavMs and TRPV2 channels with a similar architecture to the K V 7 channels, where CBD has been observed to bind at analogous sites but to produce inhibitory and potentiating effects, respectively (Pumroy et al, 2019;Sait et al, 2020).…”

Section: Discussionsupporting

confidence: 72%

“…Blue triangles (▲) indicate residues that celecoxib interacts with (Du et al, 2011). Gold triangles (▲) indicate residues that ZK‐21 interacts with (Hernandez et al, 2022). (b, c) Stylized representations of modulator interaction sites mapped onto the cryo‐EM structures of (b) hK V 7.2 (PDB: 7CR2; Li, Zhang, et al, 2021) and (c) hK V 7.1 (PDB: 6UZZ; Sun & MacKinnon, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…However, retigabine is not the only allosteric modulator that binds to this lipid‐exposed site. For instance, the anti‐inflammatory celecoxib reportedly favours a similar site to retigabine (Du et al, 2011) and a novel activator with high selectivity for hK V 7.2 (ZK‐21) was recently reported to use the same site (Hernandez et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

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Subtype‐specific modulation of human K_V7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

Pökl

Sridhar

Frampton

et al. 2023

British J Pharmacology

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Background and PurposeCannabidiol (CBD) is used clinically as an anticonvulsant. Its precise mechanism of action has remained unclear. CBD was recently demonstrated to enhance the activity of the neuronal KV7.2/7.3 channel, which may be one important contributor to CBD anticonvulsant effect. Curiously, CBD inhibits the closely related cardiac KV7.1/KCNE1 channel. Whether and how CBD affects other KV7 subtypes remains uninvestigated and the CBD interaction sites mediating these diverse effects remain unknown.Experimental ApproachHere, we used electrophysiology, molecular dynamics simulations, molecular docking and site‐directed mutagenesis to address these questions.Key ResultsWe found that CBD modulates the activity of all human KV7 subtypes and that the effects are subtype dependent. CBD enhanced the activity of KV7.2–7.5 subtypes, seen as a V50 shift towards more negative voltages or increased maximum conductance. In contrast, CBD inhibited the KV7.1 and KV7.1/KCNE1 channels, seen as a V50 shift towards more positive voltages and reduced conductance. In KV7.2 and KV7.4, we propose a CBD interaction site at the subunit interface in the pore domain that overlaps with the interaction site of other compounds, notably the anticonvulsant retigabine. However, CBD relies on other residues for its effects than the conserved tryptophan that is critical for retigabine effects. We propose a similar, though not identical CBD site in KV7.1, with a non‐conserved phenylalanine being important.Conclusions and ImplicationsWe identify novel targets of CBD, contributing to a better understanding of CBD clinical effects and provide mechanistic insights into how CBD modulates different KV7 subtypes.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Subtype‐specific modulation of human K_V7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

Pökl

Sridhar

Frampton

et al. 2023

British J Pharmacology

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“…Both of them have the potential to replace retigabine as an FDA‐approved drug. More potent, specific, and less toxic Kv7.2/3 channel activators currently under development (Hernandez et al., 2022; Liu et al., 2019; Miceli et al., 2018; Zhang et al., 2019) are also a drug option for clinical trials.…”

Section: Prospectsmentioning

confidence: 99%

The potassium channels: Neurobiology and pharmacology of tinnitus

Lai,

Gao,

Yang

2023

J of Neuroscience Research

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Tinnitus is a widespread public health issue that imposes a significant social burden. The occurrence and maintenance of tinnitus have been shown to be associated with abnormal neuronal activity in the auditory pathway. Based on this view, neurobiological and pharmacological developments in tinnitus focus on ion channels and synaptic neurotransmitter receptors in neurons in the auditory pathway. With major breakthroughs in the pathophysiology and research methodology of tinnitus in recent years, the role of the largest family of ion channels, potassium ion channels, in modulating the excitability of neurons involved in tinnitus has been increasingly demonstrated. More and more potassium channels involved in the neural mechanism of tinnitus have been discovered, and corresponding drugs have been developed. In this article, we review animal (mouse, rat, hamster, and guinea‐pig), human, and genetic studies on the different potassium channels involved in tinnitus, analyze the limitations of current clinical research on potassium channels, and propose future prospects. The aim of this review is to promote the understanding of the role of potassium ion channels in tinnitus and to advance the development of drugs targeting potassium ion channels for tinnitus.

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“…[17,18] Consequently, a possible approach to obtain safer replacements of flupirtine and retigabine is to screen for entirely new chemotypes, as done in the case of the very recently published compound ZK-21 (8, Figure 2), which has a 4-aminotetrahydroquinoline scaffold. [19] Moreover, the novel dual-mechanism K V 7 channel opener GRT-X (7) that activates both K V 7 potassium channels and the mitochondrial translocator protein (TSPO) likewise has no noteworthy structural similarities with the triaminoaryl type K V 7 channel openers. [20] Hence, new chemotypes such as 7 or 8 could represent a conceivable way to prevent the adverse effects that are presumably closely linked to the metabolically and chemically labile structure of flupirtine and retigabine.…”

mentioning

confidence: 99%

Replacing the oxidation‐sensitive triaminoaryl chemotype of problematic K_V7 channel openers: Exploration of a nicotinamide scaffold

Wurm

Bartz

Schulig

et al. 2022

Archiv der Pharmazie

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K V 7 channel openers have proven their therapeutic value in the treatment of pain as well as epilepsy and, moreover, they hold the potential to expand into additional indications with unmet medical needs. However, the clinically validated but meanwhile discontinued K V 7 channel openers flupirtine and retigabine bear an oxidation-sensitive triaminoraryl scaffold, which is suspected of causing adverse drug reactions via the formation of quinoid oxidation products. Here, we report the design and synthesis of nicotinamide analogs and related compounds that remediate the liability in the chemical structure of flupirtine and retigabine. Optimization of a nicotinamide lead structure yielded analogs with excellent K V 7.2/3 opening activity, as evidenced by EC 50 values approaching the single-digit nanomolar range. On the other hand, weighted K V 7.2/3 opening activity data including inactive compounds allowed for the establishment of structure-activity relationships and a plausible binding mode hypothesis verified by docking and molecular dynamics simulations.channels are homo-or heterotetrameric, voltage-gated potassium channels expressed in various tissues, [1] whereby especially heterotetrameric neuronal K V 7 channels predominantly composed of K V 7.2 and K V 7.3 subunits are validated pharmacological targets. [2] In general, K V 7 activation induces hyperpolarization of cell membranes, through which the ion channels contribute to controlling neuronal excitability. By increasing the action potential threshold [3] and medium afterhyperpolarization while reducing spike frequency, [4] K V 7 channels act as a "brake" for hyperexcitability. [5] Moreover, their opening probability can be influenced by small-molecule ligands, [6] making them attractive therapeutic targets, particularly for a range of neurological diseases. [5] For example, the administration of K V 7 channel openers was recently discussed for the therapy of various forms of brain damage, including chronic stress-induced brain injury (CSBI) as well as traumatic brain injury (TBI), for which currently no pharmacotherapeutic treatment options exist. In both cases, animal models suggest that reducing the underlying neuronal hyperexcitability by enhancing K V 7-mediated potassium currents might offer a protective effect. Thus, K V 7 channel activation may be a novel therapeutic intervention

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Development of an automated screen for Kv7.2 potassium channels and discovery of a new agonist chemotype

Cited by 8 publications

References 28 publications

Subtype‐specific modulation of human K_V7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

Subtype‐specific modulation of human K_V7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

The potassium channels: Neurobiology and pharmacology of tinnitus

Replacing the oxidation‐sensitive triaminoaryl chemotype of problematic K_V7 channel openers: Exploration of a nicotinamide scaffold

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Development of an automated screen for Kv7.2 potassium channels and discovery of a new agonist chemotype

Cited by 8 publications

References 28 publications

Subtype‐specific modulation of human KV7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

Subtype‐specific modulation of human KV7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

The potassium channels: Neurobiology and pharmacology of tinnitus

Replacing the oxidation‐sensitive triaminoaryl chemotype of problematic KV7 channel openers: Exploration of a nicotinamide scaffold

Contact Info

Product

Resources

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Subtype‐specific modulation of human K_V7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

Subtype‐specific modulation of human K_V7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

Replacing the oxidation‐sensitive triaminoaryl chemotype of problematic K_V7 channel openers: Exploration of a nicotinamide scaffold