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

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 23a (0.08 ± 0.04 μM) were lower, whereas no change in potency was observed for 24a (0.63 ± 0.07 μM). In addition, compared to retigabine, 23a and 24a 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 23a and 24a in comparison with retigabine. Overall, the present results highlight that the N5-alkylamidoindole moiety provides a suitable pharmacophoric scaffold for the design of chemically stable, highly potent and selective Kv7 agonists.

Kv7型钾离子通道（Kv7 K+ channels）是治疗包括癫痫在内的多种神经系统疾病的极具潜力的药理学靶点。本文针对经典Kv7激活剂瑞替加滨（retigabine）合成了42种构象受限类似物，并通过膜片钳电生理实验评估其作为Kv7激动剂的活性。与瑞替加滨的半最大效应浓度（EC50）0.93 ± 0.43 μM相比，化合物23a增强Kv7.2电流的EC50为0.08 ± 0.04 μM，显著更低；而化合物24a的EC50为0.63 ± 0.07 μM，其活性效力无明显变化。此外，相较于瑞替加滨，化合物23a与24a在激活异聚体Kv7.2/Kv7.3通道以及同聚体Kv7.4通道方面同样展现出更高的效力。分子建模研究为明确结合位点最优相互作用所需的化学特征提供了新的认识。稳定性实验证实，相较于瑞替加滨，化合物23a与24a的化学稳定性得到提升。综上，本研究结果表明，N5-烷基酰胺吲哚基团可为化学稳定、强效且具有选择性的Kv7激动剂的设计提供适宜的药效团骨架。