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Nav 1.7-selective inhibitors

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https://www.readbyqxmd.com/read/28301520/the-structure-dynamics-and-selectivity-profile-of-a-nav1-7-potency-optimised-huwentoxin-iv-variant
#1
Sassan Rahnama, Jennifer R Deuis, Fernanda C Cardoso, Venkatraman Ramanujam, Richard J Lewis, Lachlan D Rash, Glenn F King, Irina Vetter, Mehdi Mobli
Venom-derived peptides have attracted much attention as potential lead molecules for pharmaceutical development. A well-known example is Huwentoxin-IV (HwTx-IV), a peptide toxin isolated from the venom of the Chinese bird-eating spider Haplopelma schmitdi. HwTx-IV was identified as a potent blocker of a human voltage-gated sodium channel (hNaV1.7), which is a genetically validated analgesic target. The peptide was promising as it showed high potency at NaV1.7 (IC50 ~26 nM) and selectivity over the cardiac NaV subtype (NaV1...
2017: PloS One
https://www.readbyqxmd.com/read/28106092/pharmacological-characterisation-of-the-highly-nav1-7-selective-spider-venom-peptide-pn3a
#2
Jennifer R Deuis, Zoltan Dekan, Joshua S Wingerd, Jennifer J Smith, Nehan R Munasinghe, Rebecca F Bhola, Wendy L Imlach, Volker Herzig, David A Armstrong, K Johan Rosengren, Frank Bosmans, Stephen G Waxman, Sulayman D Dib-Hajj, Pierre Escoubas, Michael S Minett, Macdonald J Christie, Glenn F King, Paul F Alewood, Richard J Lewis, John N Wood, Irina Vetter
Human genetic studies have implicated the voltage-gated sodium channel NaV1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom of the tarantula Pamphobeteus nigricolor, potently inhibits NaV1.7 (IC50 0.9 nM) with at least 40-1000-fold selectivity over all other NaV subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by NaV1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically...
January 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/27130441/differential-inhibition-of-cardiac-and-neuronal-na-channels-by-the-selective-serotonin-norepinephrine-reuptake-inhibitors-duloxetine-and-venlafaxine
#3
Carsten Stoetzer, Bastian Papenberg, Thorben Doll, Marc Völker, Joerg Heineke, Marcus Stoetzer, Florian Wegner, Andreas Leffler
Duloxetine and venlafaxine are selective serotonin-norepinephrine-reuptake-inhibitors used as antidepressants and co-analgesics. While venlafaxine rather than duloxetine induce cardiovascular side-effects, neither of the substances are regarded cardiotoxic. Inhibition of cardiac Na(+)-channels can be associated with cardiotoxicity, and duloxetine was demonstrated to block neuronal Na(+)-channels. The aim of this study was to investigate if the non-life threatening cardiotoxicities of duloxetine and venlafaxine correlate with a weak inhibition of cardiac Na(+)-channels...
July 15, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27050761/subtype-selective-small-molecule-inhibitors-reveal-a-fundamental-role-for-nav1-7-in-nociceptor-electrogenesis-axonal-conduction-and-presynaptic-release
#4
Aristos J Alexandrou, Adam R Brown, Mark L Chapman, Mark Estacion, Jamie Turner, Malgorzata A Mis, Anna Wilbrey, Elizabeth C Payne, Alex Gutteridge, Peter J Cox, Rachel Doyle, David Printzenhoff, Zhixin Lin, Brian E Marron, Christopher West, Nigel A Swain, R Ian Storer, Paul A Stupple, Neil A Castle, James A Hounshell, Mirko Rivara, Andrew Randall, Sulayman D Dib-Hajj, Douglas Krafte, Stephen G Waxman, Manoj K Patel, Richard P Butt, Edward B Stevens
Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7's role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential...
2016: PloS One
https://www.readbyqxmd.com/read/26999206/analgesic-effects-of-gptx-1-pf-04856264-and-cnv1014802-in-a-mouse-model-of-nav1-7-mediated-pain
#5
Jennifer R Deuis, Joshua S Wingerd, Zoltan Winter, Thomas Durek, Zoltan Dekan, Silmara R Sousa, Katharina Zimmermann, Tali Hoffmann, Christian Weidner, Mohammed A Nassar, Paul F Alewood, Richard J Lewis, Irina Vetter
Loss-of-function mutations of Na(V)1.7 lead to congenital insensitivity to pain, a rare condition resulting in individuals who are otherwise normal except for the inability to sense pain, making pharmacological inhibition of Na(V)1.7 a promising therapeutic strategy for the treatment of pain. We characterized a novel mouse model of Na(V)1.7-mediated pain based on intraplantar injection of the scorpion toxin OD1, which is suitable for rapid in vivo profiling of Na(V)1.7 inhibitors. Intraplantar injection of OD1 caused spontaneous pain behaviors, which were reversed by co-injection with Na(V)1...
March 17, 2016: Toxins
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