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https://www.readbyqxmd.com/read/28337335/correction-to-sulfonamides-as-selective-nav1-7-inhibitors-optimizing-potency-and-pharmacokinetics-to-enable-in-vivo-target-engagement
#1
Isaac E Marx, Thomas A Dineen, Jessica Able, Christiane Bode, Howard Bregman, Margaret Chu-Moyer, Erin F DiMauro, Bingfan Du, Robert S Foti, Robert T Fremeau, Hua Gao, Hakan Gunaydin, Brian E Hall, Liyue Huang, Thomas Kornecook, Charles R Kreiman, Daniel S La, Joseph Ligutti, Min-Hwa Jasmine Lin, Dong Liu, Jeff S McDermott, Bryan D Moyer, Hanh N Nguyen, Emily A Peterson, Jonathan T Roberts, Paul Rose, Jean Wang, Beth D Youngblood, Violeta Yu, Matthew M Weiss
[This corrects the article DOI: 10.1021/acsmedchemlett.6b00243.].
March 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28324649/sulfonamides-as-selective-nav1-7-inhibitors-optimizing-potency-pharmacokinetics-and-metabolic-properties-to-obtain-atropisomeric-quinolinone-am-0466-that-affords-robust-in-vivo-activity
#2
Russell F Graceffa, Alessandro A Boezio, Jessica Able, Steven Altmann, Loren M Berry, Christiane M Boezio, John R Butler, Margaret Y Chu-Moyer, Melanie Cooke, Erin F DiMauro, Thomas A Dineen, Elma Feric Bojic, Robert S Foti, Robert T Fremeau, Angel Guzman-Perez, Hua Gao, Hakan Gunaydin, Hongbing Huang, Liyue Huang, Christopher Ilch, Michael Jarosh, Thomas Kornecook, Charles R Kreiman, Daniel S La, Joseph Ligutti, Benjamin Charles Milgram, Min-Hwa Jasmine Lin, Isaac E Marx, Hanh Nho Nguyen, Emily A Peterson, Gwen Rescourio, John Roberts, Laurie B Schenkel, Roman Shimanovich, Brian Andrew Sparling, John Stellwagen, Kristin Taborn, Karina R Vaida, Jean Wang, John T S Yeoman, Violeta L Yu, Dawn Zhu, Bryan D Moyer, Matthew M Weiss
Due to its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a novel series of atropisomeric quinolinone sulfonamide inhibitors of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms...
March 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28301520/the-structure-dynamics-and-selectivity-profile-of-a-nav1-7-potency-optimised-huwentoxin-iv-variant
#3
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/28287723/sulfonamides-as-selective-nav1-7-inhibitors-optimizing-potency-and-pharmacokinetics-while-mitigating-metabolic-liabilities
#4
Matthew M Weiss, Thomas A Dineen, Isaac E Marx, Steven Altmann, Alessandro A Boezio, Howard Bregman, Margaret Y Chu-Moyer, Erin F DiMauro, Elma Feric Bojic, Robert S Foti, Hua Gao, Russell F Graceffa, Hakan Gunaydin, Angel Guzman-Perez, Hongbing Huang, Liyue Huang, Michael Jarosh, Thomas Kornecook, Charles R Kreiman, Joseph Ligutti, Daniel S La, Min-Hwa Jasmine Lin, Dong Liu, Bryan D Moyer, Hanh Nho Nguyen, Emily A Peterson, Paul E Rose, Kristin Taborn, Beth D Youngblood, Violeta L Yu, Robert T Fremeau
Several reports have recently emerged regarding the identification of heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. The optimization of a series of internal NaV1.7 leads that address a number of metabolic liabilities including bioactivation, PXR activation, as well as CYP3A4 induction and inhibition led to the identification of potent and selective inhibitors that demonstrated favorable pharmacokinetic profiles and were devoid of the aforementioned liabilities...
March 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28277940/a-single-structurally-conserved-sumoylation-site-in-crmp2-controls-nav1-7-function
#5
Erik Thomas Dustrude, Samantha Perez-Miller, Liberty François-Moutal, Aubin Moutal, May Khanna, Rajesh Khanna
The neuronal collapsin response mediator protein 2 (CRMP2) undergoes several posttranslational modifications that codify its functions. Most recently, CRMP2 SUMOylation (addition of small ubiquitin like modifier (SUMO)) was identified as a key regulatory step within a modification program that codes for CRMP2 interaction with, and trafficking of, voltage-gated sodium channel NaV1.7. In this paper, we illustrate the utility of combining sequence alignment within protein families with structural analysis to identify, from several putative SUMOylation sites, those that are most likely to be biologically relevant...
February 28, 2017: Channels
https://www.readbyqxmd.com/read/28266963/safety-and-efficacy-of-a-topical-sodium-channel-inhibitor-tv-45070-in-patients-with-postherpetic-neuralgia-phn-a-randomized-controlled-proof-of-concept-crossover-study-with-a-subgroup-analysis-of-the-nav1-7-r1150w-genotype
#6
Nicola Price, Rostam Namdari, Judith Neville, Katie J W Proctor, Samer Kaber, Jeffery Vest, Michael Fetell, Richard Malamut, Robin P Sherrington, Simon N Pimstone, Yigal P Goldberg
OBJECTIVE: The objective was to evaluate the safety and efficacy of TV-45070 ointment, as a treatment for postherpetic neuralgia, and to explore the response in patients with the Nav1.7 R1150W gain-of-function polymorphism. MATERIALS AND METHODS: This was a randomized, placebo-controlled, 2-period, 2-treatment crossover trial. Patients with postherpetic neuralgia with moderate or greater pain received TV-45070 and placebo ointments, each applied twice daily for 3 weeks...
April 2017: Clinical Journal of Pain
https://www.readbyqxmd.com/read/28254884/a-functional-coupling-between-crmp1-and-nav1-7-for-retrograde-propagation-of-semaphorin3a-signaling
#7
Masayuki Yamane, Naoya Yamashita, Tomonobu Hida, Yoshinori Kamiya, Fumio Nakamura, Pappachan Kolattukudy, Yoshio Goshima
Semaphorin3A (Sema3A) is a secreted type of axon guidance molecules that regulates axon wiring through neuropilin-1 (NRP1) and PlexinAs (PlexAs) receptor complex. Sema3A regulates the dendritic branching through a tetrodotoxin (TTX)-sensitive retrograde axonal transport of PlexAs and Tropomyosin-related kinase A (TrkA) complex. We here demonstrate that Nav1.7, a TTX-sensitive Na(+) channel, by coupling with collapsin response mediator protein 1 (CRMP1), mediates the Sema3A-induced retrograde transport. In mouse dorsal root ganglion (DRG) neurons, Sema3A increased co-localization of PlexA4 and TrkA in the growth cones and axons...
March 2, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28243733/biophysical-and-molecular-comparison-of-sodium-current-in-cells-isolated-from-canine-atria-and-pulmonary-vein
#8
Hector Barajas-Martinez, Robert J Goodrow, Dan Hu, Payal Patel, Mayurika Desai, Brian K Panama, Jacqueline A Treat, Gary L Aistrup, Jonathan M Cordeiro
The collar of the pulmonary vein (PV) is the focal point for the initiation of atrial arrhythmias, but the mechanisms underlying how PV cells differ from neighboring left atrial tissue are unclear. We examined the biophysical and molecular properties of INa in cells isolated from the canine pulmonary sleeve and compared the properties to left atrial tissue. PV and left atrial myocytes were isolated and patch clamp techniques were used to record INa. Action potential recordings from either tissue type were made using high-resistance electrodes...
February 27, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28235406/network-topology-of-nav1-7-mutations-in-sodium-channel-related-painful-disorders
#9
Dimos Kapetis, Jenny Sassone, Yang Yang, Barbara Galbardi, Markos N Xenakis, Ronald L Westra, Radek Szklarczyk, Patrick Lindsey, Catharina G Faber, Monique Gerrits, Ingemar S J Merkies, Sulayman D Dib-Hajj, Massimo Mantegazza, Stephen G Waxman, Giuseppe Lauria
BACKGROUND: Gain-of-function mutations in SCN9A gene that encodes the voltage-gated sodium channel NaV1.7 have been associated with a wide spectrum of painful syndromes in humans including inherited erythromelalgia, paroxysmal extreme pain disorder and small fibre neuropathy. These mutations change the biophysical properties of NaV1.7 channels leading to hyperexcitability of dorsal root ganglion nociceptors and pain symptoms. There is a need for better understanding of how gain-of-function mutations alter the atomic structure of Nav1...
February 24, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/28225079/multiple-sodium-channel-isoforms-mediate-the-pathological-effects-of-pacific-ciguatoxin-1
#10
Marco C Inserra, Mathilde R Israel, Ashlee Caldwell, Joel Castro, Jennifer R Deuis, Andrea M Harrington, Angelo Keramidas, Sonia Garcia-Caraballo, Jessica Maddern, Andelain Erickson, Luke Grundy, Grigori Y Rychkov, Katharina Zimmermann, Richard J Lewis, Stuart M Brierley, Irina Vetter
Human intoxication with the seafood poison ciguatoxin, a dinoflagellate polyether that activates voltage-gated sodium channels (NaV), causes ciguatera, a disease characterised by gastrointestinal and neurological disturbances. We assessed the activity of the most potent congener, Pacific ciguatoxin-1 (P-CTX-1), on NaV1.1-1.9 using imaging and electrophysiological approaches. Although P-CTX-1 is essentially a non-selective NaV toxin and shifted the voltage-dependence of activation to more hyperpolarising potentials at all NaV subtypes, an increase in the inactivation time constant was observed only at NaV1...
February 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28216232/safety-and-efficacy-of-a-nav1-7-selective-sodium-channel-blocker-in-patients-with-trigeminal-neuralgia-a-double-blind-placebo-controlled-randomised-withdrawal-phase-2a-trial
#11
Joanna M Zakrzewska, Joanne Palmer, Valerie Morisset, Gerard Mp Giblin, Mark Obermann, Dominik A Ettlin, Giorgio Cruccu, Lars Bendtsen, Mark Estacion, Dominique Derjean, Stephen G Waxman, Gary Layton, Kevin Gunn, Simon Tate
BACKGROUND: Current standard of care for trigeminal neuralgia is treatment with the sodium channel blockers carbamazepine and oxcarbazepine, which although effective are associated with poor tolerability and the need for titration. BIIB074, a Nav1.7-selective, state-dependent sodium-channel blocker, can be administered at therapeutic doses without titration, and has shown good tolerability in healthy individuals in phase 1 studies. We therefore assessed the safety and efficacy of BIIB074 in patients with trigeminal neuralgia in a phase 2a study...
February 16, 2017: Lancet Neurology
https://www.readbyqxmd.com/read/28216001/loperamide-inhibits-sodium-channels-to-alleviate-inflammatory-hyperalgesia
#12
Ying Wu, Beiyan Zou, Lingli Liang, Min Li, Yuan-Xiang Tao, Haibo Yu, Xiaoliang Wang, Min Li
Previous studies demonstrated that Loperamide, originally known as an anti-diarrheal drug, is a promising analgesic agent primarily targeting mu-opioid receptors. However some evidences suggested that non-opioid mechanisms may be contributing to its analgesic effect. In the present study, Loperamide was identified as a Nav1.7 blocker in a pilot screen. In HEK293 cells expressing Nav1.7 sodium channels, Loperamide blocked the resting state of Nav1.7 channels (IC50 = 1.86 ± 0.11 μM) dose-dependently and reversibly...
February 16, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28162808/fgf13-selectively-regulates-heat-nociception-by-interacting-with-nav1-7
#13
Liu Yang, Fei Dong, Qing Yang, Pai-Feng Yang, Ruiqi Wu, Qing-Feng Wu, Dan Wu, Chang-Lin Li, Yan-Qing Zhong, Ying-Jin Lu, Xiaoyang Cheng, Fu-Qiang Xu, Limin Chen, Lan Bao, Xu Zhang
The current knowledge about heat nociception is mainly confined to the thermosensors, including the transient receptor potential cation channel V1 expressed in the nociceptive neurons of dorsal root ganglion (DRG). However, the loss of thermosensors only partially impairs heat nociception, suggesting the existence of undiscovered mechanisms. We found that the loss of an intracellular fibroblast growth factor (FGF), FGF13, in the mouse DRG neurons selectively abolished heat nociception. The noxious heat stimuli could not evoke the sustained action potential firing in FGF13-deficient DRG neurons...
February 22, 2017: Neuron
https://www.readbyqxmd.com/read/28150151/structure-based-assessment-of-disease-related-mutations-in-human-voltage-gated-sodium-channels
#14
REVIEW
Weiyun Huang, Minhao Liu, S Frank Yan, Nieng Yan
Voltage-gated sodium (Nav) channels are essential for the rapid upstroke of action potentials and the propagation of electrical signals in nerves and muscles. Defects of Nav channels are associated with a variety of channelopathies. More than 1000 disease-related mutations have been identified in Nav channels, with Nav1.1 and Nav1.5 each harboring more than 400 mutations. Nav channels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Nav channels are required to understand their function and disease mechanisms...
February 1, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28148645/nonlinear-effects-of-hyperpolarizing-shifts-in-activation-of-mutant-nav1-7-channels-on-resting-membrane-potential
#15
Mark Estacion, Stephen G Waxman
The Nav1.7 sodium channel is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons. Gain-of-function mutations that cause the painful disorder inherited erythromelalgia (IEM) shift channel activation in a hyperpolarizing direction. When expressed within DRG neurons, these mutations produce a depolarization of resting membrane potential (RMP). The biophysical basis for the depolarized RMP has to date not been established. To explore the effect on RMP of the shift in activation associated with a prototypical IEM mutation (L858H), we used dynamic clamp models that represent graded shifts that fractionate the effect of the mutation on activation voltage-dependence...
February 1, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28143690/inhibition-of-veratridine-induced-delayed-inactivation-of-the-voltage-sensitive-sodium-channel-by-synthetic-analogs-of-crambescin-b
#16
Tadaaki Tsukamoto, Yukie Chiba, Atsuo Nakazaki, Yuki Ishikawa, Yoshiki Nakane, Yuko Cho, Mari Yotsu-Yamashita, Toshio Nishikawa, Minoru Wakamori, Keiichi Konoki
Crambescin B carboxylic acid, a synthetic analog of crambescin B, was recently found to inhibit the voltage-sensitive sodium channels (VSSC) in a cell-based assay using neuroblastoma Neuro 2A cells. In the present study, whole-cell patch-clamp recordings were conducted with three heterologously expressed VSSC subtypes, Nav1.2, Nav1.6 and Nav1.7, in a human embryonic kidney cell line HEK293T to further characterize the inhibition of VSSC by crambescin B carboxylic acid. Contrary to the previous observation, crambescin B carboxylic acid did not inhibit peak current evoked by depolarization from the holding potential of -100mV to the test potential of -10mV in the absence or presence of veratridine (VTD)...
January 19, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28138042/control-of-neurotransmission-by-nav1-7-in-human-guinea-pig-and-mouse-airway-parasympathetic-nerves
#17
Michaela Kocmalova, Marian Kollarik, Brendan J Canning, Fei Ru, Robert A Herbstromer, Sonya Meeker, Silvia Fonquerna, Monica Aparici, Montserrat Miralpeix, Xian Chi, Baolin Li, Ben Wilenkin, Jeff McDermott, Eric Nisenbaum, Jeff Krajewski, Bradley J Undem
Little is known about the voltage-gated sodium channels (NaVs) that control neurotransmission in the parasympathetic nervous system. We evaluated the expression of the α subunits of each of the nine NaVs in human, guinea pig, and mouse airway parasympathetic ganglia. We combined this information with a pharmacological analysis of selective NaV blockers on parasympathetic contractions of isolated airway smooth muscle. As would be expected from previous studies, tetrodotoxin potently blocked the parasympathetic responses in the airways of each species...
January 30, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28123009/distribution-of-ttx-sensitive-voltage-gated-sodium-channels-in-primary-sensory-endings-of-mammalian-muscle-spindles
#18
Dario Ivan Carrasco, Jacob A Vincent, Timothy C Cope
Knowledge of the molecular mechanisms underlying signaling of mechanical stimuli by muscle spindles remains incomplete. In particular, the ionic conductances that sustain tonic firing during static muscle stretch are unknown. We hypothesized that tonic firing by spindle afferents depends on sodium persistent inward current (INaP), and we tested for the necessary presence of the appropriate voltage-gated sodium (NaV) channels in primary sensory endings. We began study of the NaV1.6 isoform, selected both for its capacity to produce INaP and for its presence in other mechanosensors that fire tonically...
January 25, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28119481/lacosamide-inhibition-of-nav1-7-voltage-gated-sodium-channels-slow-binding-to-fast-inactivated-states
#19
Sooyeon Jo, Bruce P Bean
Lacosamide is an antiseizure agent that targets voltage-dependent sodium channels. Previous experiments have suggested that lacosamide is unusual in binding selectively to the slow-inactivated state of sodium channels, in contrast to drugs like carbamazepine and phenytoin, which bind tightly to fast-inactivated states. Using heterologously expressed human Nav1.7 sodium channels, we examined the state-dependent effects of lacosamide. Lacosamide induced a reversible shift in the voltage dependence of fast inactivation studied with 100-millisecond prepulses, suggesting binding to fast-inactivated states...
April 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28118359/the-ampk-activator-a769662-blocks-voltage-gated-sodium-channels-discovery-of-a-novel-pharmacophore-with-potential-utility-for-analgesic-development
#20
Marina N Asiedu, Chongyang Han, Sulayman D Dib-Hajj, Stephen G Waxman, Theodore J Price, Gregory Dussor
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...
2017: PloS One
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