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ID: ALA4257569
Journal: Bioorg Med Chem Lett
Title: Novel KV7 ion channel openers for the treatment of epilepsy and implications for detrusor tissue contraction.
Authors: Seefeld MA, Lin H, Holenz J, Downie D, Donovan B, Fu T, Pasikanti K, Zhen W, Cato M, Chaudhary KW, Brady P, Bakshi T, Morrow D, Rajagopal S, Samanta SK, Madhyastha N, Kuppusamy BM, Dougherty RW, Bhamidipati R, Mohd Z, Higgins GA, Chapman M, Rouget C, Lluel P, Matsuoka Y.
Abstract: Neuronal voltage-gated potassium channels, KV7s, are the molecular mediators of the M current and regulate membrane excitability in the central and peripheral neuronal systems. Herein, we report novel small molecule KV7 openers that demonstrate anti-seizure activities in electroshock and pentylenetetrazol-induced seizure models without influencing Rotarod readouts in mice. The anti-seizure activity was determined to be proportional to the unbound concentration in the brain. KV7 channels are also expressed in the bladder smooth muscle (detrusor) and activation of these channels may cause localized undesired effects. Therefore, the impact of individual KV7 isoforms was investigated in human detrusor tissue using a panel of KV7 openers with distinct activity profiles among KV7 isoforms. KCNQ4 and KCNQ5 mRNA were highly expressed in detrusor tissue, yet a compound that has significantly reduced activity on homomeric KV7.4 did not reduce detrusor contraction. This may suggest that the homomeric KV7.4 channel plays a less significant role in bladder contraction and further investigation is needed.
CiteXplore: 30327146