Abstracts

Rationale: The voltage-gated Kv7.2-Kv7.5 channels are broadly expressed in the central nervous system, where they, among other functions, control the excitability of neurons by acting as a "brake" on repeated action potential discharges. Thus, pharmacological activation of neuronal Kv7 channels has proven to be a successful therapeutic strategy within partial-onset seizures by use of the Kv7 activator retigabine (Gunthorpe et al, 2012). Interestingly, activation of Kv7 channels also holds promise as a therapeutic strategy within psychiatric disorders such as schizophrenia (Sotty et al, 2009) and depression (Friedman et al, 2016).

Methods: In the present study, we have characterized the pharmacological profile of the novel, pan-selective Kv7.2-7.5 opener Lu AA41178, using both in vitro assays and a broad range of in vivo assays related to epilepsy, schizophrenia, and depression.

Results: Using two-electrode voltage clamp in Xenopus oocytes expressing human Kv7.2-Kv7.5 Lu AA41178 was confirmed to be a pan-selective activator of Kv7 channels. When applying a voltage ramp protocol the activation threshold of Kv7.2+Kv7.3, Kv7.4 and Kv7.5 was significantly left-shifted in the presence of increasing concentrations of Lu AA41178 (0.3-30 µM). Importantly, Lu AA41178 did not display inhibitory effects on human Kv7.1 channels stably expressed in CHO cells, suggesting no impact on cardiac repolarization safety. 
_x000D_ Next, we tested Lu AA41178 in preclinical models of neurological and psychiatric disorders. In the maximum electroshock threshold test (MEST) subcutaneous pre-treatment of mice with Lu AA41178 significantly increased the electroconvulsive shock threshold, thus demonstrating an anticonvulsant effect. In the mouse  model of behavioral despair, Lu AA41178 significantly reduced immobility time to the same extent as the positive control, imipramine. Additionally, in ventral tegmental area (VTA) brain slices from mice subjected to chronic social defeat stress (CSDS) we tested the impact of Lu AA41178 on neuronal firing as assessed with whole-cell patch clamping. Here, the increased activity of VTA dopamine neurons of CSDS animals could be reversed by Lu AA41178. Behavioral testing of Lu AA41178 was accompanied by plasma and brain exposure sampling, revealing minimum effective plasma levels below 1000 ng/mL.

Conclusions: In summary, Lu AA41178 is a potent activator of neuronal Kv7 channels demonstrating efficacy in animal models of epilepsy, schizophrenia and depression. Thus, it may serve as a valuable tool for exploring the role of Kv7 channels in both neurological and psychiatric disorders.

Funding: H. Lundbeck A/S