Inhibition of Nav1.7 channel by a novel blocker QLS-81 for alleviation of neuropathic pain.

Acta Pharmacologica Sinica
He-Ling NiuKeWei Wang

Abstract

Voltage-gated sodium channel Nav1.7 robustly expressed in peripheral nociceptive neurons has been considered as a therapeutic target for chronic pain, but there is no selective Nav1.7 inhibitor available for therapy of chronic pain. Ralfinamide has shown anti-nociceptive activity in animal models of inflammatory and neuropathic pain and is currently under phase III clinical trial for neuropathic pain. Based on ralfinamide, a novel small molecule (S)-2-((3-(4-((2-fluorobenzyl) oxy) phenyl) propyl) amino) propanamide (QLS-81) was synthesized. Here, we report the electrophysiological and pharmacodynamic characterization of QLS-81 as a Nav1.7 channel inhibitor with promising anti-nociceptive activity. In whole-cell recordings of HEK293 cells stably expressing Nav1.7, QLS-81 (IC50 at 3.5 ± 1.5 μM) was ten-fold more potent than its parent compound ralfinamide (37.1 ± 2.9 μM) in inhibiting Nav1.7 current. QLS-81 inhibition on Nav1.7 current was use-dependent. Application of QLS-81 (10 μM) caused a hyperpolarizing shift of the fast and slow inactivation of Nav1.7 channel about 7.9 mV and 26.6 mV, respectively, and also slowed down the channel fast and slow inactivation recovery. In dissociated mouse DRG neurons, QLS-81 (10 μM) inhibite...Continue Reading

References

May 19, 2001·American Journal of Human Genetics·L ClaesP De Jonghe
Nov 14, 2002·Regional Anesthesia and Pain Medicine·Michael F Mulroy
May 9, 2003·Cellular and Molecular Neurobiology·Parker L AndersenAdil J Nazarali
Nov 10, 2005·Trends in Molecular Medicine·Stephen G Waxman, Sulayman Dib-Hajj
Mar 24, 2006·Nature·Michael C Sanguinetti, Martin Tristani-Firouzi
Dec 15, 2006·Nature·James J CoxC Geoffrey Woods
Jan 26, 2010·Trends in Pharmacological Sciences·Frank Bosmans, Kenton J Swartz
Mar 20, 2010·Pflügers Archiv : European journal of physiology·Karin Jurkat-RottFrank Lehmann-Horn
Nov 17, 2010·Nature Reviews. Neurology·Jin-Sung ChoiStephen G Waxman
Mar 31, 2012·Pediatric Cardiology·Weihua Song, Weinian Shou
Dec 13, 2012·Nature Reviews. Neuroscience·Sulayman D Dib-HajjStephen G Waxman
May 1, 2015·Journal of Medicinal Chemistry·Manuel de Lera Ruiz, Richard L Kraus
Dec 18, 2015·Annals of Neurology·Elena GardellaYvonne G Weber
Mar 5, 2016·Profiles of Drug Substances, Excipients, and Related Methodology·S T Alrashood
Sep 3, 2016·Current Topics in Membranes·M-R GhovanlooP C Ruben
Dec 9, 2017·Journal of Pharmacological Sciences·Xiaolei WangXin Zhao
Dec 10, 2017·Methods in Molecular Biology·Serena BoccellaLivio Luongo
Feb 7, 2018·European Journal of Pharmacology·Xiaonan LiangRuibin Su
Aug 11, 2018·Journal of Cardiovascular Pharmacology and Therapeutics·Bo QiuYanfang Xu
Feb 8, 2019·Proceedings of the National Academy of Sciences of the United States of America·Phuong T NguyenVladimir Yarov-Yarovoy
Feb 24, 2019·Neuron·Lucy A McDermottDavid L Bennett
May 28, 2019·Drug Discovery Today·Lei XuTingjun Hou
Jul 16, 2019·British Journal of Anaesthesia·Henning HermannsRobert Werdehausen
Dec 11, 2019·Handbook of Experimental Pharmacology·Yani Liu, KeWei Wang
Jul 1, 2020·Pflügers Archiv : European journal of physiology·Mark D Baker, Mohammed A Nassar

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