Novel KV7 ion channel openers for the treatment of epilepsy and implications for detrusor tissue contraction

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 23-24; pp. 3793 - 3797
• Main Authors: Seefeld, Mark A., Lin, Hong, Holenz, Joerg, Downie, Dave, Donovan, Brian, Fu, Tingting, Pasikanti, Kishore, Zhen, Wei, Cato, Matthew, Chaudhary, Khuram W., Brady, Pat, Bakshi, Tania, Morrow, Dwight, Rajagopal, Sridharan, Samanta, Swapan Kumar, Madhyastha, Naveena, Kuppusamy, Bharathi Mohan, Dougherty, Robert W., Bhamidipati, Ravi, Mohd, Zainuddin, Higgins, Guy A., Chapman, Mark, Rouget, Céline, Lluel, Philippe, Matsuoka, Yasuji
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 15.12.2018
• Subjects: Bladder; Epilepsy; KCNQ; Opener; KCNQ; Bladder; Epilepsy; Opener
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.09.036

[Display omitted] •Novel pan-Kv7 openers for the treatment of epilepsy are discussed.•Compounds from two series of Kv7 openers show efficacy in PTZ and MES-T seizure models.•Bladder contraction is associated with pan-Kv7 activity, but perhaps not with homomeric Kv7.4 activity as reported. 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.