What are Kv7 potassium channel openers and how do they work?

Kv7 potassium channel openers are a class of drugs that increase the activity of Kv7 (also known as KCNQ) potassium channels. They play important roles in regulating the excitability of nerve and muscle cells. By opening these channels, these drugs help stabilize cell membranes and reduce abnormal electrical activity.

Kv7 potassium channel openers are currently being studied for treating several disorders, especially epilepsy and related neurological conditions. In this article, we will review how they work and potential therapeutic applications.

Mechanism of Action: How Do Kv7 Potassium Channel Openers Work?

Kv7 potassium channels are voltage-gated channels present in various tissues, including the brain, heart, and smooth muscle. These channels control the flow of potassium ions across cell membranes, which is essential for maintaining the "resting potential" that keeps neurons and muscle cells stable.

In the brain, Kv7.2 and Kv7.3 subtypes are particularly important for stopping neurons from becoming overactive. When these channels are deficient or not working properly, neurons can become excessively excitable, increasing the risk of seizures and other neurological disorders.

Kv7 channel openers work by decreasing the likelihood that neurons will fire inappropriately. They bind to specific parts of the channel and enhance potassium flow out of the cell. This hyperpolarizes the membrane, making it less likely that the neuron will be stimulated to fire. As a result, the drugs act as a "brake" on excessive neuronal activity.

Clinical Candidates and Evidence

Several Kv7 potassium channel openers are being studied and are in clinical development. Notable candidates include azetukalner and retigabine. Below we summarize key clinical data supporting the therapeutic potential of these Kv7 potassium channel openers.

Retigabine

Retigabine, also known as ezogabine, was the first approved drug in this class for epilepsy. Retigabine was shown to be effective for drug-resistant seizures in clinical studies. It was FDA approved as brand name Potiga in 2011 for add-on treatment of partial-onset seizures in patients 18 years and older who haven’t adequately responded to several alternative treatments.

After its approval, the FDA published a safety alert on pigmentation-related side effects impacting the skin and eyes, as well as potential vision changes. It was withdrawn from the market in 2017.

Azetukalner

Azetukalner (XEN1101) is a novel, second-generation Kv7.2/7.3 channel opener now in phase 3 clinical trials for focal and generalized seizures, as well as major depressive disorder and bipolar depression. Azetukalner shows improved potency, selectivity, and a better safety profile over earlier Kv7 openers. Initial studies demonstrate robust efficacy for treating difficult-to-control seizures and are promising for mood disorders.

• Azetukalner’s efficacy in focal seizure treatment was evaluated in an 8-week phase 2b randomized, double-blind, placebo-controlled trial at 97 sites in North America and Europe involving 325 adults with drug-resistant focal seizures. The primary analysis showed dose-dependent seizure frequency reduction across all azetukalner groups compared to placebo (P < 0.001). The median percent reduction from baseline in monthly FOS frequency was 52.8% for 25 mg, 46.4% for 20 mg, and 33.2% for 10 mg, compared with 18.2% for placebo.
• No new safety signals were identified from the ongoing 7-year open-label extension study (X-TOLE) as of publication in April 2025.
• The X-NOVA phase 2 study evaluated azetukalner for efficacy and safety in adults with moderate to severe major depressive disorder (MDD). The primary outcome, change in MADRS (Montgomery-Åsberg Depression Rating Scale) score at week 6, was a mean reduction of –13.90 points for placebo, –15.61 for 10 mg, and –16.94 for 20 mg; the reduction for 20 mg vs placebo was clinically meaningful (–3.04 points) but not statistically significant (P = .14).

Related questions

• How to sleep while taking Cymbalta?
• What is Exxua?
• How long do venlafaxine withdrawal symptoms last?

Other Candidates

Compounds such as BHV-7000, pynegabine, and CB-003 are also under development but have less clinical data available at this time. These compounds are currently in phase 1 studies assessing safety and pharmacokinetics.

Therapeutic Applications of Kv7 Potassium Channel Openers

The main focus of Kv7 channel openers has been on neurological and psychiatric disorders, but their unique mechanism may allow for broader therapeutic use:

• Epilepsy: The primary clinical use, targeting focal and generalized seizures, particularly in drug-resistant cases.
• Major Depressive Disorder: Recent clinical trials suggest potential benefit in mood disorders, especially with azetukalner showing some early efficacy in relieving symptoms like anhedonia.
• Smooth Muscle Disorders: There is scientific interest in treating conditions such as hypertension, urinary incontinence, and even preterm labor due to the role of Kv7 channels in regulating vascular and smooth muscle tone.
• Neuroprotection: Preclinical studies suggest Kv7 openers may help prevent nerve damage in certain contexts, such as chemotherapy-induced peripheral neuropathy.

What are the Side Effects of Kv7 Potassium Channel Openers?

Safety profiles can vary between compounds, but common and potential side effects include:

• Central nervous system effects: Dizziness, drowsiness, and confusion have been reported with retigabine and azetukalner. In a phase 2 clinical study, 18% of patients taking azetukalner for MDD reported dizziness and 11% reported drowsiness.
• Pigmentation changes: Retigabine was associated with skin, retinal, and mucosal pigmentation, leading to its market withdrawal. Early studies of azetukalner haven’t identified pigmentary changes or major safety issues.
• Urinary retention or hesitation: Caused by action on bladder smooth muscle, this side effect has been reported by a small number of patients taking retigabine and azetukalner.
• Gastrointestinal effects: Constipation has been observed due to modulation of intestinal motility.

While newer agents like azetukalner have so far not shown the pigment-related side effects, larger studies and long-term data is needed to confirm that it doesn’t occur.

Summary

Kv7 potassium channel openers offer an innovative approach to managing neuronal and muscle hyperactivity by stabilizing cell membranes through targeted potassium ion regulation. Clinical progress, especially with azetukalner, underscores the promise of this class for epilepsy, depression, and possibly other conditions. Ongoing research continues to improve selectivity and minimize adverse effects. Upcoming phase 3 clinical trials are expected to provide additional insight into the effectiveness and safety of this therapy.

Read next

See also:

Related medical questions

• When is the best time to take Lexapro? Morning vs Night Dosing
• 8 Cymbalta Side Effects: Should I be Concerned?
• Lexapro vs Zoloft: How do they compare?
• How long for an increased dose of Zoloft to work?
• How long does it take for Lexapro to work?
• Why should you take aripiprazole in the morning?
• How long do Abilify withdrawal symptoms last?
• What antidepressants are usually taken with Abilify?
• What do Cymbalta brain zaps feel like?
• Prozac vs Xanax: How do they compare?
• How long does Trintellix withdrawal last?
• Does Lexapro cause night sweats?
• Vraylar vs Abilify - How do they compare?
• Does Remeron help with sleep?
• Can Trintellix be split or cut in half?
• Does Auvelity work better than Wellbutrin?
• Does Trintellix cause sexual side effects?
• What is Rexulti used for and how well does it work?
• Why does Rexulti cause weight gain?
• How does Vraylar compare with Seroquel?
• Auvelity vs. Wellbutrin: Effectiveness for Depression?
• Do Vraylar (cariprazine) side effects go away?
• Does vitamin D help with depression?
• Can I take Cymbalta (duloxetine) and Trintellix (vortioxetine) together?

Related support groups

• Major Depressive Disorder (542 questions, 1,392 members)
• Seizures (163 questions, 795 members)

Medical Disclaimer