title: The AMPK Activator A769662 Blocks Voltage-Gated Sodium Channels: Discovery of a Novel Pharmacophore with Potential Utility for Analgesic Development.
abstract: Voltage-gated sodium channels (VGSC) regulate neuronal excitability by governing action potential (AP) generation and propagation. Recent studies have revealed that AMP-activated protein kinase (AMPK) activators decrease sensory neuron excitability, potentially by preventing sodium (Na+) channel phosphorylation by kinases such as ERK or via modulation of translation regulation pathways. The direct positive allosteric modulator A769662 displays substantially greater efficacy than other AMPK activators in decreasing sensory neuron excitability suggesting additional mechanisms of action. Here, we show that A769662 acutely inhibits AP firing stimulated by ramp current injection in rat trigeminal ganglion (TG) neurons. PT1, a structurally dissimilar AMPK activator that reduces nerve growth factor (NGF) -induced hyperexcitability, has no influence on AP firing in TG neurons upon acute application. In voltage-clamp recordings, application of A769662 reduces VGSC current amplitudes. These findings, based on acute A769662 application, suggest a direct channel blocking effect. Indeed, A769662 dose-dependently blocks VGSC in rat TG neurons and in Nav1.7-transfected cells with an IC50 of ~ 10 μM. A769662 neither displayed use-dependent inhibition nor interacted with the local anesthetic (LA) binding site. Popliteal fossa administration of A769662 decreased noxious thermal responses with a peak effect at 5 mins demonstrating an analgesic effect. These data indicate that in addition to AMPK activation, A769662 acts as a direct blocker/modulator of VGSCs, a potential mechanism enhancing the analgesic property of this compound.
authors.affiliation: University of Arizona, Department of Pharmacology, Tucson, Arizona, United States of America.|University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, Texas, United States of America.
authors.forename: Marina N
authors.initials: MN
authors.lastname: Asiedu
authors.affiliation: Yale School of Medicine, Department of Neurology, Center for Neuroscience and Regeneration Research, and Veterans Administration Connecticut Healthcare System, Rehabilitation Research Center, West Haven, Connecticut, United States of America.
authors.forename: Chongyang
authors.initials: C
authors.lastname: Han
authors.affiliation: Yale School of Medicine, Department of Neurology, Center for Neuroscience and Regeneration Research, and Veterans Administration Connecticut Healthcare System, Rehabilitation Research Center, West Haven, Connecticut, United States of America.
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.affiliation: Yale School of Medicine, Department of Neurology, Center for Neuroscience and Regeneration Research, and Veterans Administration Connecticut Healthcare System, Rehabilitation Research Center, West Haven, Connecticut, United States of America.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
authors.affiliation: University of Arizona, Department of Pharmacology, Tucson, Arizona, United States of America.|University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, Texas, United States of America.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
authors.affiliation: University of Arizona, Department of Pharmacology, Tucson, Arizona, United States of America.|University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, Texas, United States of America.
authors.forename: Gregory
authors.initials: G
authors.lastname: Dussor
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects*; D000700:Analgesics / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001713:Biphenyl Compounds; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006358:Hot Temperature / Q000009:adverse effects; D006801:Humans; D008297:Male; D008687:Metformin / Q000494:pharmacology; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000187:drug effects* / Q000235:genetics; D009431:Neural Conduction / Q000187:drug effects; D010146:Pain / Q000188:drug therapy; D018408:Patch-Clamp Techniques; D011753:Pyrones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000378:metabolism; D000077185:Resveratrol; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000201:enzymology; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D012668:Trigeminal Ganglion / Q000187:drug effects; D062368:meta-Aminobenzoates / Q000494:pharmacology
chemical_list: C000611054:2-chloro-5-((5-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-4-oxo-2-thiazolyl)amino)benzoic acid; D000700:Analgesics; D000779:Anesthetics, Local; D001713:Biphenyl Compounds; D062556:NAV1.7 Voltage-Gated Sodium Channel; D011753:Pyrones; D011993:Recombinant Fusion Proteins; C486866:SCN9A protein, human; D026941:Sodium Channel Blockers; D013267:Stilbenes; D013844:Thiazoles; D013876:Thiophenes; D062368:meta-Aminobenzoates; D008687:Metformin; D055372:AMP-Activated Protein Kinases; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile; D000077185:Resveratrol