Beyond Retigabine: Design, Synthesis, and Pharmacological Characterization of a Potent and Chemically Stable Neuronal Kv7 Channel Activator with Anticonvulsant Activity

Abstract

Neuronal Kv7 channels represent important pharmacological targets for hyperexcitability disorders including epilepsy. Retigabine is the prototype Kv7 activator clinically approved for seizure treatment; however, severe side effects associated with long-term use have led to its market discontinuation. Building upon the recently described cryoEM structure of Kv7.2 complexed with retigabine and on previous structure–activity relationship studies, a small library of retigabine analogues has been designed, synthesized, and characterized for their Kv7 opening ability using both fluorescence- and electrophysiology-based assays. Among all tested compounds, 60 emerged as a potent and photochemically stable neuronal Kv7 channel activator. Compared to retigabine, compound 60 displayed a higher brain/plasma distribution ratio, a longer elimination half-life, and more potent and effective anticonvulsant effects in an acute seizure model in mice. Collectively, these data highlight compound 60 as a promising lead compound for the development of novel Kv7 activators for the treatment of hyperexcitability diseases.

The Voltage-Sensor S4 Rises to the Occasion in KCNQ2 Channel Activation

“…The only available potassium channel opener, retigabine, has poor specificity among KCNQ channel subunits and causes undue off-target side effects. 10 Retigabine causes a hyperpolarizing shift in the voltage-dependence of activation, which the authors propose may be beneficial in mutations like R214W but not in other mutations. Other potassium channel openers that target the voltage-sensing domain are under development and may be more applicable to mutations like R198Q.…”

Advances in Epilepsy: Mechanisms, Clinical Trials, and Drug Therapies

“…11 K V 7 (KCNQ channel) is the seventh subfamily of VGPCs, which consists of five members (K V 7.1− 7.5) that each have a different tissue distribution and physiological function. 19 KCNQ1 is restricted to cardiac tissues, 20 and KCNQ2−5 are mainly expressed in the central and peripheral nervous systems. Therefore, they are often referred to as neuronal KCNQs.…”

“…Compound 11 showed six times more potent compared to flupirtine and is devoid of the potential for azaquinone diimine formation . Compound 12 is a potent and photochemically stable neuronal Kv7 channel activator, which displayed a higher B/P distribution ratio, no photoinduced dimer formation, a longer plasma half-life in vivo and higher potent and effective anticonvulsant effects in an acute seizure model in mice . Compound 13 (P-RTG) is an RTG analogue developed by incorporating a propargyl group at the N position of the RTG linker.…”

“…150 Compound 12 is a potent and photochemically stable neuronal Kv7 channel activator, which displayed a higher B/P distribution ratio, no photoinduced dimer formation, a longer plasma halflife in vivo and higher potent and effective anticonvulsant effects in an acute seizure model in mice. 19 Compound 13 (P-RTG) is an RTG analogue developed by incorporating a propargyl group at the N position of the RTG linker. The B/P concentration ratio of 13 increased to 2.3 (RTG = 0.16).…”

“…A variety of seizure-related potassium channel mutations have been found, such as KCNQ2, KCNQ3, KCNA1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNT1, and KCTD7 . K V 7 (KCNQ channel) is the seventh subfamily of VGPCs, which consists of five members (K V 7.1–7.5) that each have a different tissue distribution and physiological function . KCNQ1 is restricted to cardiac tissues, and KCNQ2–5 are mainly expressed in the central and peripheral nervous systems.…”