From Pan-Reactive K(V)7 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.