From Pan-Reactive KV7 Channel Opener to Subtype Selective Opener/Inhibitor by Addition of a Methyl Group

The voltage-gated potassium channels of the K V 7 family (K V 7.1–5) play important roles in controlling neuronal excitability and are therefore attractive targets for treatment of CNS disorders linked to hyperexcitability. One of the main challenges in developing K V 7 channel active drugs has been to identify compounds capable of discriminating between the neuronally expressed subtypes (K V 7.2–5), aiding the identification of the subunit composition of K V 7 currents in various tissues, and possessing better therapeutic potential for particular indications. By taking advantage of the structure-activity relationship of acrylamide K V 7 channel openers and the effects of these compounds on mutant K V 7 channels, we have designed and synthesized a novel K V 7 channel modulator with a unique profile. The compound, named SMB-1, is an inhibitor of K V 7.2 and an activator of K V 7.4. SMB-1 inhibits K V 7.2 by reducing the current amplitude and increasing the time constant for the slow component of the activation kinetics. The activation of K V 7.4 is seen as an increase in the current amplitude and a slowing of the deactivation kinetics. Experiments studying mutant channels with a compromised binding site for the K V 7.2–5 opener retigabine indicate that SMB-1 binds within the same pocket as retigabine for both inhibition of K V 7.2 and activation of K V 7.4. SMB-1 may serve as a valuable tool for K V 7 channel research and may be used as a template for further design of better subtype selective K V 7 channel modulators. A compound with this profile could hold novel therapeutic potential such as the treatment of both positive and cognitive symptoms in schizophrenia.