Therapeutic potential of small molecules that block receptor-induced Kv7/M-current suppression in neuroprotection, seizures, and pain

Br J Pharmacol. 2026 Apr 9. doi: 10.1111/bph.70432. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Neuronal Kv7 channels generate low voltage-gated potassium currents known as the M-current. The M-current is transiently suppressed by activation of Gq-coupled receptors, caused by a loss of an essential cofactor phosphatidylinositol 4,5-bisphosphate (PIP₂) from the Kv7 channel complex, thereby increasing neuronal excitability. M-current suppression-mediated neuronal overexcitation contributes to seizures, pain, and excitotoxicity. However, therapeutic strategies targeting M-current suppression remain underutilised. We hypothesised that small-molecule binding to a state-dependent cytosolic pocket in Kv7 channels stabilise the ion-conducting conformation and mitigate M-current suppression.

EXPERIMENTAL APPROACH: The Kv7 cytosolic pocket was used as a target site for in silico screening of 3D molecular libraries of clinically used compounds. Candidate compounds were functionally validated using patch-clamp recordings in CHO cells heterologously expressing Kv7 channels and human M₁ muscarinic receptors. Selected model compounds were further characterised for effects on modulation of Kv7 channels, neuroprotection, and in vivo outcomes using pilocarpine-induced seizure and formalin paw inflammatory pain models.

KEY RESULTS: Several compounds reduced oxotremorine-M-induced Kv7.2 current suppression. Dabigatran etexilate, carvedilol, and nebivolol were selected as model compounds for further study. These compounds (1) attenuated M₁ muscarinic receptor-induced suppression across all Kv7 subtypes and endogenous M-currents, (2) protected neurons from glutamate- or hydrogen peroxide-induced neurotoxicity, and (3) reduced inflammatory pain responses. Dabigatran etexilate additionally mitigated pilocarpine-induced seizures.

CONCLUSION AND IMPLICATIONS: A new class of Kv7 channel modulators reduce M-current suppression and are efficacious in several disease models. This mechanism provides a rationale for developing novel therapeutics targeting this cytosolic site.

PMID:41956525 | DOI:10.1111/bph.70432