title: ML297 (VU0456810), the first potent and selective activator of the GIRK potassium channel, displays antiepileptic properties in mice.
abstract: The G-protein activated, inward-rectifying potassium (K(+)) channels, "GIRKs", are a family of ion channels (Kir3.1-Kir3.4) that has been the focus of intense research interest for nearly two decades. GIRKs are comprised of various homo- and heterotetrameric combinations of four different subunits. These subunits are expressed in different combinations in a variety of regions throughout the central nervous system and in the periphery. The body of GIRK research implicates GIRK in processes as diverse as controlling heart rhythm, to effects on reward/addiction, to modulation of response to analgesics. Despite years of GIRK research, very few tools exist to selectively modulate GIRK channels' activity and until now no tools existed that potently and selectively activated GIRKs. Here we report the development and characterization of the first truly potent, effective, and selective GIRK activator, ML297 (VU0456810). We further demonstrate that ML297 is active in two in vivo models of epilepsy, a disease where up to 40% of patients remain with symptoms refractory to present treatments. The development of ML297 represents a truly significant advancement in our ability to selectively probe GIRK's role in physiology as well as providing the first tool for beginning to understand GIRK's potential as a target for a diversity of therapeutic indications.
authors.affiliation: Vanderbilt Institute of Chemical Biology, ‡Department of Pharmacology, §Department of Chemistry, ∥Vanderbilt Specialized Chemistry Center, ⊥Division of Anesthesiology, and #Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Kristian
authors.initials: K
authors.lastname: Kaufmann
authors.forename: Ian
authors.initials: I
authors.lastname: Romaine
authors.forename: Emily
authors.initials: E
authors.lastname: Days
authors.forename: Conrado
authors.initials: C
authors.lastname: Pascual
authors.forename: Adam
authors.initials: A
authors.lastname: Malik
authors.forename: Liya
authors.initials: L
authors.lastname: Yang
authors.forename: Bende
authors.initials: B
authors.lastname: Zou
authors.forename: Yu
authors.initials: Y
authors.lastname: Du
authors.forename: Greg
authors.initials: G
authors.lastname: Sliwoski
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morrison
authors.forename: Jerod
authors.initials: J
authors.lastname: Denton
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Gary A
authors.initials: GA
authors.lastname: Sulikowski
authors.forename: Xinmin Simon
authors.initials: XS
authors.lastname: Xie
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D020013:Calcium Signaling / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004597:Electroshock / Q000009:adverse effects; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000819:agonists*; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D010433:Pentylenetetrazole / Q000633:toxicity; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects; D011994:Recombinant Proteins / Q000187:drug effects; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D014635:Valproic Acid / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; C587714:CID 56642816; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D010671:Phenylurea Compounds; D011720:Pyrazoles; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; C111435:metabotropic glutamate receptor 8; D014635:Valproic Acid; D010433:Pentylenetetrazole