XXVI National Meeting in Medicinal Chemistry -XII Young Medicinal Chemists’ Symposium

The Kv7 K+ channels play a fundamental role in controlling neuronal excitability, representing an attractive pharmacological target for the treatment of different neurological disorders, particularly epilepsy.1,2 Retigabine, the only antiepileptic drug approved for human use, acts as Kv7.2/7.3 agonist. However, it has been withdrawn from the market due to the formation of unsafe oxidized metabolites.3 In order to improve both chemical and metabolic stability, we designed and synthesized three series of conformationally restricted analogues of retigabine (Figure 1). The pharmacological effects of these series were investigated by electrophysiological and patch-clamp experiments. The indole-based derivatives 23a (EC50 = 0.08 ± 0.04 μM) and 24a (EC50 = 0.63 ± 0.07 μM) acted as potent Kv7.2 agonists with improved potency and efficacy than retigabine (EC50 = 0.93 ± 0.43 μM).