title: Discovery and SAR of a novel series of GIRK1/2 and GIRK1/4 activators.
abstract: This Letter describes a novel series of GIRK activators identified through an HTS campaign. The HTS lead was a potent and efficacious dual GIRK1/2 and GIRK1/4 activator. Further chemical optimization through both iterative parallel synthesis and fragment library efforts identified dual GIRK1/2 and GIRK1/4 activators as well as the first examples of selective GIRK1/4 activators. Importantly, these compounds were inactive on GIRK2 and other non-GIRK1 containing GIRK channels, and SAR proved shallow.
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramos-Hunter
authors.forename: Darren W
authors.initials: DW
authors.lastname: Engers
authors.forename: Kristian
authors.initials: K
authors.lastname: Kaufmann
authors.forename: Yu
authors.initials: Y
authors.lastname: Du
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.forename: Gary A
authors.initials: GA
authors.lastname: Sulikowski
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D051379:Mice; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015335:Molecular Probes
keywords: Activators; GIRK; K(ir)3.x; Thallium flux
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