Nappi, Piera (2021) Beyond retigabine: Design, identification, and pharmacological characterization of novel neuronal Kv7 channel activators. [Tesi di dottorato]

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The Kv7 subfamily of voltage-gated potassium channels includes 5 members (Kv7.1-Kv7.5) having distinct expression patterns and physiological roles. Kv7.2 and Kv7.3 subunits are mainly expressed in the nervous system, where they underlie the so-called M-current (IKM), a sub-threshold K+ current controlling action potential generation. Neuronal Kv7 potassium channels are critical regulators of neuronal excitability; indeed, loss-of-function mutations in the genes encoding for Kv7.2 and Kv7.3 are responsible for a wide spectrum of early-onset epilepsies. On the other hand, retigabine is a strong activator of the Kv7 currents, representing the first antiepileptic drug acting on Kv7 channels. Approved in 2011 for adjunctive therapy in adults showing drug-resistant partial onset seizures with or without secondary generalization, retigabine suppresses neuronal hyperexcitability by shifting the Kv7.2/3 current activation threshold toward more hyperpolarized potentials, thereby increasing their maximal current. Unfortunately, retigabine, suffers from considerable drawbacks including poor selectivity for Kv7 subtypes, short half-life, poor brain penetration and chemical instability. The latter, represents one of the main clinical concern over retigabine; light exposure may cause photodegradation and oxidation, leading to dimer formation, which induces retinal and mucocutaneous blue-gray discoloration in patients taking the drugs more than 3 years. For these reasons, leading to a progressively reduced use of the drug, the manufacturing company (GSK) has decided to withdraw the drug from the market since June 2017. Since no KCNQ activator is currently available for clinical use, this work originates from our effort to identify novel and safer IKM activators. For this purpose, we synthesized a library of 41 retigabine derivatives, structurally characterized by modification that aim to overcome at least some of the limitations of retigabine and we developed a fluorescence-based assay to rapidly evaluate the effect of these derivatives on Kv7 channels

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