Synthesis and Pharmacological Characterization of Conformationally Restricted Retigabine Analogues as Novel Neuronal Kv7 Channel Activators

Abstract

Kv7 K⁺ channels represent attractive pharmacological targets for the treatment of different neurological disorders, including epilepsy. In this paper, 42 conformationally restricted analogues of the prototypical Kv7 activator retigabine have been synthesized and tested by electrophysiological patch-clamp experiments as Kv7 agonists. When compared to retigabine (0.93 ± 0.43 μM), the EC₅₀s for Kv7.2 current enhancements by compound <b>23a</b> (0.08 ± 0.04 μM) were lower, whereas no change in potency was observed for <b>24a</b> (0.63 ± 0.07 μM). In addition, compared to retigabine, <b>23a</b> and <b>24a</b> showed also higher potency in activating heteromeric Kv7.2/Kv7.3 and homomeric Kv7.4 channels. Molecular modeling studies provided new insights into the chemical features required for optimal interaction at the binding site. Stability studies evidenced improved chemical stability of <b>23a</b> and <b>24a</b> in comparison with retigabine. Overall, the present results highlight that the <i>N</i>5-alkylamidoindole moiety provides a suitable pharmacophoric scaffold for the design of chemically stable, highly potent and selective Kv7 agonists.