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

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journal contribution
posted on 2019-12-24, 11:29 authored by Carmine Ostacolo, Francesco Miceli, Veronica Di Sarno, Piera Nappi, Nunzio Iraci, Maria Virginia Soldovieri, Tania Ciaglia, Paolo Ambrosino, Vincenzo Vestuto, Anna Lauritano, Simona Musella, Giacomo Pepe, Manuela Giovanna Basilicata, Michele Manfra, Diego Romano Perinelli, Ettore Novellino, Alessia Bertamino, Isabel M. Gomez-Monterrey, Pietro Campiglia, Maurizio Taglialatela
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.