Recent research suggests that KCNQ isoforms, particularly the KCNQ4 and KCNQ5 subtypes expressed in smooth muscle cells, are involved in both establishing and maintaining resting membrane potentials and regulating smooth muscle contractility. Retigabine (RTG) is a first-in-class antiepileptic drug that potentiates neuronal KCNQ potassium channels, but poor subtype selectivity limits its further application as a pharmacological tool. In this study, we improved the subtype specificity of retigabine by altering the N-1/3 substituents and discovered several compounds that show better selectivity for KCNQ4 and KCNQ5 channels. Among these compounds, 10g is highly selective for KCNQ4 and KCNQ5 channels without potentiating KCNQ1 and KCNQ2 channels. These results are an advance in the exploration of small molecule modifiers that selectively activate different KCNQ isoforms. The developed compounds could also serve as new pharmacological tools for elucidating the function of KCNQ channels natively expressed in various tissues.