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

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 (PIP 2 ) 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 M 1 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 M 1 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.