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 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.

The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding

“…Future efforts comparing the effects of both DN and GOF variants on the neuronal network in vitro and in vivo are necessary to understand how Kv7.2 regulates neurodevelopment and can potentially open new doors for innovative therapeutic tools. Lastly, the development of Kv7 channel blockers and openers overcoming some of the pharmacokinetic and pharmacodynamic limitations shown by the available drugs (all of which have been synthesized and started to be developed well before the discovery of the KCNQ gene subfamily and the description of their multiple pathophysiological roles) could not only be beneficial for patients suffering from KCNQ2-B and KCNQ2-E but could also positively impact patients affected with multiple neurodegenerative disorders (Wainger et al, 2014;Kumar et al, 2016;Ostacolo et al, 2020).…”

Synthetic resin acid derivatives selectively open the hKV7.2/7.3 channel and prevent epileptic seizures

“…11 RTG was associated with several side effects, which were possibly due to activation of Kv7.4 and Kv7.5 channels in various organs. 12 In addition, RTG caused a blue-gray mucocutaneous discoloration, which depends on photo instability of a metabolite. 13 Due to the side effects, the use of RTG was limited and it was withdrawn from the market in 2017.…”

“…It binds to the central pore domain of the channel, specifically to a tryptophan in S5, which is conserved among the hK V 7.2–7.5 channels (green residue in Figure 1A; molecular structure in Figure 1B); therefore, RTG is not selective for hK V 7.2/7.3 but also activates the hK V 7.4 and hK V 7.5 channels 11 . RTG was associated with several side effects, which were possibly due to activation of Kv7.4 and Kv7.5 channels in various organs 12 . In addition, RTG caused a blue‐gray mucocutaneous discoloration, which depends on photo instability of a metabolite 13 .…”

“…In addition, RTG caused a blue‐gray mucocutaneous discoloration, which depends on photo instability of a metabolite 13 . Due to the side effects, the use of RTG was limited and it was withdrawn from the market in 2017 12 . Despite these drawbacks, RTG validated the hK V 7.2/7.3 channel as an antiseizure target, thereby supporting the development of new hK V 7.2/7.3 channel activators as potential antiseizure drugs.…”

Detrusor Smooth Muscle KV7 Channels: Emerging New Regulators of Urinary Bladder Function

“…They include (1) retigabine and flupirtine, both pan-specific activators of K V 7.2-K V 7.5 channels; (2) ICA-069673, a selective activator of K V 7.2/K V 7.3 channels; (3) ML213, a preferential activator of K V 7.2, K V 7.2/K V 7.3, and K V 7.4 channels; (4) XE991 and linopirdine, pan-selective inhibitors of K V 7.1-K V 7.5 channels ( Miceli et al, 2008 , 2018 ; Yu et al, 2010 , 2011 ; Amato et al, 2011 ; Barrese et al, 2018b ). More recently, the next generation of subtype-specific and selective modulators for K V 7.2/K V 7.3 and K V 7.4/K V 7.5 channels has been described ( Liu et al, 2019 ; Osuma et al, 2019 ; Zhang et al, 2019 ; Ostacolo et al, 2020 ). These compounds provide an excellent opportunity to determine the functions of K V 7 channels subtypes in DSM and elsewhere.…”