Anxiolytic effects of maxipost (BMS-204352) and retigabine via activation of neuronal Kv7 channels

Neuronal K(v)7 channels are recognized as potential drug targets for treating hyperexcitability disorders such as pain, epilepsy, and mania. Hyperactivity of the amygdala has been described in clinical and preclinical studies of anxiety, and therefore, neuronal K(v)7 channels may be a relevant target for this indication. In patch-clamp electrophysiology on cell lines expressing K(v)7 channel subtypes, Maxipost (BMS-204352) exerted positive modulation of all neuronal K(v)7 channels, whereas its R-enantiomer was a negative modulator. By contrast, at the K(v)7.1 and the large conductance Ca2+-activated potassium channels, the two enantiomers showed the same effect, namely, negative and positive modulation at the two channels, respectively. At GABA(A) receptors (alpha(1)beta(2)gamma(2s) and alpha(2)beta(2)gamma(2s)) expressed in Xenopus oocytes, BMS-204352 was a negative modulator, and the R-enantiomer was a positive modulator. The observation that the S- and R-forms exhibited opposing effects on neuronal K(v)7 channel subtypes allowed us to assess the potential role of K(v)7 channels in anxiety. In vivo, BMS-204352 (3-30 mg/kg) was anxiolytic in the mouse zero maze and marble burying models of anxiety, with the effect in the burying model antagonized by the R-enantiomer (3 mg/kg). Likewise, the positive K(v)7 channel modulator retigabine was anxiolytic in both models, and its effect in the burying model was blocked by the K v 7 channel inhibitor 10,10-bis-pyridin-4-ylmethyl-10H-anthracen-9-one (XE-991) (1 mg/kg). Doses at which BMS-204352 and retigabine induce anxiolysis could be dissociated from effects on sedation or memory impairment. In conclusion, these in vitro and in vivo studies provide compelling evidence that neuronal K v 7 channels are a target for developing novel anxiolytics.