title: From pan-reactive KV7 channel opener to subtype selective opener/inhibitor by addition of a methyl group.
abstract: The voltage-gated potassium channels of the KV7 family (KV7.1-5) 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 KV7 channel active drugs has been to identify compounds capable of discriminating between the neuronally expressed subtypes (KV7.2-5), aiding the identification of the subunit composition of KV7 currents in various tissues, and possessing better therapeutic potential for particular indications. By taking advantage of the structure-activity relationship of acrylamide KV7 channel openers and the effects of these compounds on mutant KV7 channels, we have designed and synthesized a novel KV7 channel modulator with a unique profile. The compound, named SMB-1, is an inhibitor of KV7.2 and an activator of KV7.4. SMB-1 inhibits KV7.2 by reducing the current amplitude and increasing the time constant for the slow component of the activation kinetics. The activation of KV7.4 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 KV7.2-5 opener retigabine indicate that SMB-1 binds within the same pocket as retigabine for both inhibition of KV7.2 and activation of KV7.4. SMB-1 may serve as a valuable tool for KV7 channel research and may be used as a template for further design of better subtype selective KV7 channel modulators. A compound with this profile could hold novel therapeutic potential such as the treatment of both positive and cognitive symptoms in schizophrenia.
authors: Division of Neuroscience Drug Discovery, H. Lundbeck A/S, Copenhagen, Denmark; Department of Biomedical Sciences and Danish National Research Foundation Centre for Cardiac Arrhythmia, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Sigrid Marie
authors: SM
authors: Blom
authors: Division of Discovery Chemistry and DMPK, H. Lundbeck A/S, Copenhagen, Denmark.
authors: Mario
authors: M
authors: Rottländer
authors: Division of Discovery Chemistry and DMPK, H. Lundbeck A/S, Copenhagen, Denmark.
authors: Jan
authors: J
authors: Kehler
authors: Division of Discovery Chemistry and DMPK, H. Lundbeck A/S, Copenhagen, Denmark.
authors: Christoffer
authors: C
authors: Bundgaard
authors: Department of Biomedical Sciences and Danish National Research Foundation Centre for Cardiac Arrhythmia, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Nicole
authors: N
authors: Schmitt
authors: Division of Neuroscience Drug Discovery, H. Lundbeck A/S, Copenhagen, Denmark.
authors: Henrik Sindal
authors: HS
authors: Jensen
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D006801:Humans; D051656:KCNQ Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051658:KCNQ2 Potassium Channel / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D049990:Membrane Transport Modulators / Q000737:chemistry* / Q000494:pharmacology*; D020125:Mutation, Missense; D014982:Xenopus laevis
chemical_list: D051656:KCNQ Potassium Channels; D051658:KCNQ2 Potassium Channel; C117367:KCNQ4 protein, human; C412231:KCNQ5 protein, human; D049990:Membrane Transport Modulators