Discovery of Novel Retigabine Derivatives as Potent KCNQ4 and KCNQ5 Channel Agonists with Improved Specificity

Abstract

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.

Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss

“…As other KCNQ channels are involved in the physiology of diverse tissues and may also be associated with diseases, lack of specificity would lead to unwanted side-effects. As such, the selectivity for KCNQ4 could be achieved by the further refinement of existing compounds, as shown previously [ 76 ]. Based on the delineation of the crucial residues of the specific binding of retigabine with KCNQ4 and the molecular details of its activation [ 71 ], the discovery and optimization of related chemicals would be accelerated.…”

“…Wang et al reported several compounds that were made by modifying retigabine and showed better selectivity for KCNQ4 and KCNQ5 [ 76 ]. For instance, a N-1/3 substitution resulted in improved specificity for KCNQ4 and KCNQ5 compared with naïve retigabine [ 76 ].…”

“…Wang et al reported several compounds that were made by modifying retigabine and showed better selectivity for KCNQ4 and KCNQ5 [ 76 ]. For instance, a N-1/3 substitution resulted in improved specificity for KCNQ4 and KCNQ5 compared with naïve retigabine [ 76 ]. Especially, 10 g of one of those derivatives showed the best potency for KCNQ4 and KCNQ5 with EC 50 values of 0.78 and 1.68 μM, respectively, and had a minimal effect on homomeric KCNQ2 [ 76 ].…”

“…For instance, a N-1/3 substitution resulted in improved specificity for KCNQ4 and KCNQ5 compared with naïve retigabine [ 76 ]. Especially, 10 g of one of those derivatives showed the best potency for KCNQ4 and KCNQ5 with EC 50 values of 0.78 and 1.68 μM, respectively, and had a minimal effect on homomeric KCNQ2 [ 76 ]. More specifically, 10 μM of 10 g of this compound was reported to increase the currents of KCNQ4 and KCNQ5 by 6.4- and 4.6-fold, respectively [ 76 ].…”

“…Especially, 10 g of one of those derivatives showed the best potency for KCNQ4 and KCNQ5 with EC 50 values of 0.78 and 1.68 μM, respectively, and had a minimal effect on homomeric KCNQ2 [ 76 ]. More specifically, 10 μM of 10 g of this compound was reported to increase the currents of KCNQ4 and KCNQ5 by 6.4- and 4.6-fold, respectively [ 76 ]. Further modification of this compound may lead to a drug with better specificity for KCNQ4 over KCNQ5.…”