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https://www.readbyqxmd.com/read/28710467/human-ipsc-derived-cardiomyocytes-cultured-in-3d-engineered-heart-tissue-show-physiological-upstroke-velocity-and-sodium-current-density
#1
Marc D Lemoine, Ingra Mannhardt, Kaja Breckwoldt, Maksymilian Prondzynski, Frederik Flenner, Bärbel Ulmer, Marc N Hirt, Christiane Neuber, András Horváth, Benjamin Kloth, Hermann Reichenspurner, Stephan Willems, Arne Hansen, Thomas Eschenhagen, Torsten Christ
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising tool for drug testing and modelling genetic disorders. Abnormally low upstroke velocity is a current limitation. Here we investigated the use of 3D engineered heart tissue (EHT) as a culture method with greater resemblance to human heart tissue in comparison to standard technique of 2D monolayer (ML) format. INa was measured in ML or EHT using the standard patch-clamp technique. INa density was ~1.8 fold larger in EHT (-18...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28684121/discovery-of-a-biarylamide-series-of-potent-state-dependent-nav1-7-inhibitors
#2
Laurie B Schenkel, Erin F DiMauro, Hanh N Nguyen, Nagasree Chakka, Bingfan Du, Robert S Foti, Angel Guzman-Perez, Michael Jarosh, Daniel S La, Joseph Ligutti, Benjamin C Milgram, Bryan D Moyer, Emily A Peterson, John Roberts, Violeta L Yu, Matthew M Weiss
The NaV1.7 ion channel has garnered considerable attention as a target for the treatment of pain. Herein we detail the discovery and structure-activity relationships of a novel series of biaryl amides. Optimization led to the identification of several state-dependent, potent and metabolically stable inhibitors which demonstrated promising levels of selectivity over NaV1.5 and good rat pharmacokinetics. Compound 18, which demonstrated preferential inhibition of a slow inactivated state of NaV1.7, was advanced into a rat formalin study where upon reaching unbound drug levels several fold over the rat NaV1...
June 26, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28683073/high-throughput-electrophysiological-assays-for-voltage-gated-ion-channels-using-syncropatch-768pe
#3
Tianbo Li, Gang Lu, Eugene Y Chiang, Tania Chernov-Rogan, Jane L Grogan, Jun Chen
Ion channels regulate a variety of physiological processes and represent an important class of drug target. Among the many methods of studying ion channel function, patch clamp electrophysiology is considered the gold standard by providing the ultimate precision and flexibility. However, its utility in ion channel drug discovery is impeded by low throughput. Additionally, characterization of endogenous ion channels in primary cells remains technical challenging. In recent years, many automated patch clamp (APC) platforms have been developed to overcome these challenges, albeit with varying throughput, data quality and success rate...
2017: PloS One
https://www.readbyqxmd.com/read/28682065/discovery-of-clinical-candidate-4-2-5-amino-1h-pyrazol-4-yl-4-chlorophenoxy-5-chloro-2-fluoro-n-1-3-thiazol-4-ylbenzenesulfonamide-pf-05089771-design-and-optimization-of-diaryl-ether-aryl-sulfonamides-as-selective-inhibitors-of-nav1-7
#4
Nigel Alan Swain, Dave Batchelor, Serge Beaudoin, Bruce M Bechle, Paul A Bradley, Alan D Brown, Bruce Brown, Ken J Butcher, Richard P Butt, Mark L Chapman, Stephen Denton, David Ellis, Sebastien Galan, Stephen M Gaulier, Ben S Greener, Marcel J de Groot, Mel S Glossop, Ian K Gurrell, Jo Hannam, Matthew S Johnson, Zhixin Lin, Christopher J Markworth, Brian E Marron, David S Millan, Shoko Nakagawa, Andy Pike, David Printzenhoff, David J Rawson, Sarah J Ransley, Steven M Reister, Kosuke Sasaki, R Ian Storer, Paul Anthony Stupple, Christopher W West
A series of acidic diaryl ether heterocyclic sulfonamides that are potent and sub-type selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over non-metabolic routes of clearance, variable clearance in pre-clinical species and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics...
July 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28658526/reverse-pharmacogenomics-carbamazepine-normalizes-activation-and-attenuates-thermal-induced-hyperexcitability-of-sensory-neurons-due-to-nav1-7-mutation-i234t
#5
Yang Yang, Talia Adi, Philip Effraim, Lubin Chen, Sulayman D Dib-Hajj, Stephen G Waxman
BACKGROUND AND PURPOSE: Pharmacotherapy for pain currently involves trial-and-error. A previous study on inherited erythromelalgia (a genetic model of neuropathic pain due to mutations in voltage-gated sodium channel Nav1.7) used genomics, structural modeling, biophysical and pharmacological analyses to guide pharmacotherapy, and showed that carbamazepine normalizes voltage-dependence of activation of the Nav1.7-S241T mutant channel, reducing pain in patients carrying this mutation. However, whether this approach is applicable to other Nav mutations is still unknown...
June 28, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28645932/a-functional-nav1-7-navab-chimera-with-a-reconstituted-high-affinity-protx-ii-binding-site
#6
Ramkumar Rajamani, Sophie Wu, Iyoncy Rodrigo, Mian Gao, Simon Low, Lisa Megson, David Wensel, Rick Pieschl, Debra Post-Munson, John Watson, David R Langley, Michael Ahlijanian, Linda Bristow, James Herrington
NaV1.7 is genetically implicated in human pain perception. Rare gain of function mutations in NaV1.7 lead to spontaneous pain in humans whereas loss of function mutations result in congenital insensitivity to pain (CIP). Hence, agents that specifically modulate the function of NaV1.7 have the potential to yield novel therapeutics to treat pain. The complexity of the channel and the challenges to generate recombinant cell lines with high NaV1.7 expression have led to a templated target strategy approach employing chimeras with the bacterial channel, NavAb...
June 23, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28635651/effects-of-tetrodotoxin-in-mouse-models-of-visceral-pain
#7
Rafael González-Cano, Miguel Ángel Tejada, Antonia Artacho-Cordón, Francisco Rafael Nieto, José Manuel Entrena, John N Wood, Cruz Miguel Cendán
Visceral pain is very common and represents a major unmet clinical need for which current pharmacological treatments are often insufficient. Tetrodotoxin (TTX) is a potent neurotoxin that exerts analgesic actions in both humans and rodents under different somatic pain conditions, but its effect has been unexplored in visceral pain. Therefore, we tested the effects of systemic TTX in viscero-specific mouse models of chemical stimulation of the colon (intracolonic instillation of capsaicin and mustard oil) and intraperitoneal cyclophosphamide-induced cystitis...
June 21, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28629594/the-discovery-of-benzoxazine-sulfonamide-inhibitors-of-nav1-7-tools-that-bridge-efficacy-and-target-engagement
#8
Daniel S La, Emily A Peterson, Christiane Bode, Alessandro A Boezio, Howard Bregman, Margaret Y Chu-Moyer, James Coats, Erin F DiMauro, Thomas A Dineen, Bingfan Du, Hua Gao, Russell Graceffa, Hakan Gunaydin, Angel Guzman-Perez, Robert Fremeau, Xin Huang, Christopher Ilch, Thomas J Kornecook, Charles Kreiman, Joseph Ligutti, Min-Hwa Jasmine Lin, Jeff S McDermott, Isaac Marx, David J Matson, Stefan I McDonough, Bryan D Moyer, Hanh Nho Nguyen, Kristin Taborn, Violeta Yu, Matthew M Weiss
The voltage-gated sodium channel NaV1.7 has received much attention from the scientific community due to compelling human genetic data linking gain- and loss-of-function mutations to pain phenotypes. Despite this genetic validation of NaV1.7 as a target for pain, high quality pharmacological tools facilitate further understanding of target biology, establishment of target coverage requirements and subsequent progression into the clinic. Within the sulfonamide class of inhibitors, reduced potency on rat NaV1...
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28621020/conservation-of-alternative-splicing-in-sodium-channels-reveals-evolutionary-focus-on-release-from-inactivation-and-structural-insights-into-gating
#9
A Liavas, G Lignani, S Schorge
Voltage-gated sodium channels are critical for neuronal activity, and highly intolerant to variation. Even mutations that cause subtle changes in the activity these channels are sufficient to cause devastating inherited neurological diseases, such as epilepsy and pain. However, these channels do vary in healthy tissue. Alternative splicing modifies sodium channels, but the functional relevance and adaptive significance of this splicing remain poorly understood. Here we use a conserved alternate exon encoding part of the first domain of sodium channels to compare how splicing modifies different channels, and to ask whether the functional consequences of this splicing have been preserved in different genes...
June 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28609318/biochemical-and-pharmacological-characterization-of-a-mice-model-of-complex-regional-pain-syndrome
#10
Vaskar Das, Jeffrey S Kroin, Mario Moric, Asokumar Buvanendran
BACKGROUND AND OBJECTIVES: Complex regional pain syndrome is a challenging disease to treat. Recently, a mouse fracture model of complex regional pain syndrome has been developed that has many signs of the clinical syndrome. However, many aspects of the sensory neuron biochemistry and behavioral and pharmacological characterization of this model remain to be clarified. METHODS: Mice were randomly assigned to fracture/cast or control (naive) groups. Fracture/cast mice underwent a closed distal tibia facture, with hindlimb wrapped in casting tape for 3 weeks...
July 2017: Regional Anesthesia and Pain Medicine
https://www.readbyqxmd.com/read/28582470/estradiol-upregulates-voltage-gated-sodium-channel-1-7-in-trigeminal-ganglion-contributing-to-hyperalgesia-of-inflamed-tmj
#11
Rui-Yun Bi, Zhen Meng, Peng Zhang, Xue-Dong Wang, Yun Ding, Ye-Hua Gan
BACKGROUND: Temporomandibular disorders (TMDs) have the highest prevalence in women of reproductive age. The role of estrogen in TMDs and especially in TMDs related pain is not fully elucidated. Voltage-gated sodium channel 1.7 (Nav1.7) plays a prominent role in pain perception and Nav1.7 in trigeminal ganglion (TG) is involved in the hyperalgesia of inflamed Temporomandibular joint (TMJ). Whether estrogen could upregulate trigeminal ganglionic Nav1.7 expression to enhance hyperalgesia of inflamed TMJ remains to be explored...
2017: PloS One
https://www.readbyqxmd.com/read/28562485/antihyperalgesic-effect-by-herpes-vector-mediated-knockdown-of-nav1-7-sodium-channels-after-skin-incision
#12
Andreas Eisenried, Michael Klukinov, David C Yeomans, Alexander Z Tzabazis
Postincisional hyperalgesia and allodynia play an important role in perioperative medicine. NaV1.7 sodium channel has proven to be a key player in several pain states, including acute, inflammatory, and neuropathic pain. This study investigated the effects of silencing NaV1.7 through Herpes-based gene therapy with an antisense transcript on pain states after incision of the skin in rodents. Seventy-six Balb/C mice were subdivided into six groups and were treated with no virus, control virus, or NaV1.7 antisense vector before lateral hindpaw skin incision or sham procedure...
August 2, 2017: Neuroreport
https://www.readbyqxmd.com/read/28548111/corrigendum-pharmacological-characterisation-of-the-highly-nav1-7-selective-spider-venom-peptide-pn3a
#13
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
No abstract text is available yet for this article.
May 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28530638/sodium-channel-nav1-9-mutations-associated-with-insensitivity-to-pain-dampen-neuronal-excitability
#14
Jianying Huang, Carlos G Vanoye, Alison Cutts, Y Paul Goldberg, Sulayman D Dib-Hajj, Charles J Cohen, Stephen G Waxman, Alfred L George
Voltage-gated sodium channel (NaV) mutations cause genetic pain disorders that range from severe paroxysmal pain to a congenital inability to sense pain. Previous studies on NaV1.7 and NaV1.8 established clear relationships between perturbations in channel function and divergent clinical phenotypes. By contrast, studies of NaV1.9 mutations have not revealed a clear relationship of channel dysfunction with the associated and contrasting clinical phenotypes. Here, we have elucidated the functional consequences of a NaV1...
June 30, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28522215/blocking-voltage-gated-sodium-channels-as-a-strategy-to-suppress-pathological-cough
#15
REVIEW
Hui Sun, Marian Kollarik, Bradley J Undem
Pathological cough is thought to be secondary to inappropriate activation of vagal sensory nerves. Sensory nerves can be activated by a large number of disparate stimuli. The most relevant stimuli to block for effective anti-tussive therapy likely depend on the specific underlying pathology that is leading to the coughing. Blocking voltage-gated sodium channels (NaV) will prevent action potential initiation and conduction and therefore prevent sensory communication between the airways and brainstem. In so doing, they would be expected to inhibit evoked cough independently of the nature of the stimulus and underlying pathology...
May 15, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28490900/complex-management-of-a-patient-with-refractory-primary-erythromelalgia-lacking-a-scn9a-mutation
#16
Sarah A Low, Wendye Robbins, Vivianne L Tawfik
A 41-year-old woman presented with burning and erythema in her extremities triggered by warmth and activity, which was relieved by applying ice. Extensive workup was consistent with adult-onset primary erythromelalgia (EM). Several pharmacological treatments were tried including local anesthetics, capsaicin, ziconotide, and dantrolene, all providing 24-48 hours of relief followed by symptom flare. Interventional therapies, including peripheral and sympathetic ganglion blocks, also failed. Thus far, clonidine and ketamine have been the only effective agents for our patient...
2017: Journal of Pain Research
https://www.readbyqxmd.com/read/28480765/targeting-dorsal-root-ganglia-and-primary-sensory-neurons-for-the-treatment-of-chronic-pain
#17
REVIEW
Temugin Berta, Yawar Qadri, Ping-Heng Tan, Ru-Rong Ji
Currently the treatment of chronic pain is inadequate and compromised by debilitating central nervous system side effects. Here we discuss new therapeutic strategies that target dorsal root ganglia (DRGs) in the peripheral nervous system for a better and safer treatment of chronic pain. Areas covered: The DRGs contain the cell bodies of primary sensory neurons including nociceptive neurons. After painful injuries, primary sensory neurons demonstrate maladaptive molecular changes in DRG cell bodies and in their axons...
July 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28473457/pharmacologic-characterization-of-amg8379-a-potent-and-selective-small-molecule-sulfonamide-antagonist-of-the-voltage-gated-sodium-channel-nav1-7
#18
Thomas J Kornecook, Ruoyuan Yin, Stephen Altmann, Xuhai Be, Virginia Berry, Christopher P Ilch, Michael Jarosh, Danielle Johnson, Josie H Lee, Sonya G Lehto, Joseph Ligutti, Dong Liu, Jason Luther, David Matson, Danny Ortuno, John Roberts, Kristin Taborn, Jinti Wang, Matthew M Weiss, Violeta Yu, Dawn X D Zhu, Robert T Fremeau, Bryan D Moyer
Potent and selective antagonists of the voltage-gated sodium channel NaV1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380. Here we show that AMG8379 potently blocks human NaV1.7 channels with an IC50 of 8.5 nM and endogenous tetrodotoxin (TTX)-sensitive sodium channels in dorsal root ganglion (DRG) neurons with an IC50 of 3.1 nM in whole-cell patch clamp electrophysiology assays using a voltage protocol that interrogates channels in a partially inactivated state...
July 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28465103/benzoxazolinone-aryl-sulfonamides-as-potent-selective-nav1-7-inhibitors-with-in-vivo-efficacy-in-a-preclinical-pain-model
#19
Joseph E Pero, Michael A Rossi, Hannah D G F Lehman, Michael J Kelly, James J Mulhearn, Scott E Wolkenberg, Matthew J Cato, Michelle K Clements, Christopher J Daley, Tracey Filzen, Eleftheria N Finger, Yun Gregan, Darrell A Henze, Aneta Jovanovska, Rebecca Klein, Richard L Kraus, Yuxing Li, Annie Liang, John M Majercak, Jacqueline Panigel, Mark O Urban, Jixin Wang, Ying-Hong Wang, Andrea K Houghton, Mark E Layton
Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1...
June 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28450535/sodium-channel-nav1-8-underlies-ttx-resistant-axonal-action-potential-conduction-in-somatosensory-c-fibers-of-distal-cutaneous-nerves
#20
Amanda H Klein, Alina Vyshnevska, Timothy V Hartke, Roberto De Col, Joseph L Mankowski, Brian Turnquist, Frank Bosmans, Peter W Reeh, Martin Schmelz, Richard W Carr, Matthias Ringkamp
Voltage-gated sodium (NaV) channels are responsible for the initiation and conduction of action potentials within primary afferents. The nine NaV channel isoforms recognized in mammals are often functionally divided into tetrodotoxin (TTX)-sensitive (TTX-s) channels (NaV1.1-NaV1.4, NaV1.6-NaV1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (NaV1.8 and NaV1.9) inhibited by millimolar concentrations, with NaV1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different NaV channel isoforms are distributed along the peripheral and central branches of their bifurcated axons...
May 17, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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