title: Myrsinane, Premyrsinane, and Cyclomyrsinane Diterpenes from Euphorbia falcata as Potassium Ion Channel Inhibitors with Selective G Protein-Activated Inwardly Rectifying Ion Channel (GIRK) Blocking Effects.
abstract: GIRK channels are activated by a large number of G protein-coupled receptors and regulate the electrical activity of neurons, cardiac atrial myocytes, and β-pancreatic cells. Abnormalities in GIRK channel function have been implicated in the pathophysiology of neuropathic pain, drug addiction, and cardiac arrhythmias. In the heart, GIRK channels are selectively expressed in the atrium, and their activation inhibits pacemaker activity, thereby slowing the heart rate. In the present study, 19 new diterpenes, falcatins A-S (1-19), and the known euphorprolitherin D (20) were isolated from Euphorbia falcata. The compounds were assayed on stable transfected HEK-hERG (Kv11.1) and HEK-GIRK1/4 (Kir3.1 and Kir3.4) cells. Blocking activity on GIRK channels was exerted by 13 compounds (61-83% at 10 μM), and, among them, five possessed low potency on the hERG channel (4-20% at 10 μM). These selective activities suggest that myrsinane-related diterpenes are potential lead compounds for the treatment of atrial fibrillation.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vasas
authors.forename: Peter
authors.initials: P
authors.lastname: Forgo
authors.affiliation: Rytmion Ltd. , Ősz u. 27, H-6724 Szeged, Hungary.|Department of Pharmacology and Pharmacotherapy, University of Szeged , Dóm tér 12, H-6720 Szeged, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Orvos
authors.affiliation: Rytmion Ltd. , Ősz u. 27, H-6724 Szeged, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Tálosi
authors.forename: Attila
authors.initials: A
authors.lastname: Csorba
authors.affiliation: Department of Botany, Faculty of Agricultural and Food Sciences, Széchenyi István University , Vár 2, H-9200 Mosonmagyaróvár, Hungary.
authors.forename: Gyula
authors.initials: G
authors.lastname: Pinke
authors.forename: Judit
authors.initials: J
authors.lastname: Hohmann
mesh_terms: D000818:Animals; D004224:Diterpenes / Q000737:chemistry / Q000145:classification / Q000302:isolation & purification / Q000494:pharmacology; D028481:Euphorbia / Q000737:chemistry*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000145:classification / Q000187:drug effects*; D006321:Heart; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure; D009474:Neurons / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled
chemical_list: D004224:Diterpenes; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D026902:Potassium Channel Blockers; D043562:Receptors, G-Protein-Coupled