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https://www.readbyqxmd.com/read/28924048/a-mutant-of-the-bmk-antitumor-analgesic-peptide-exhibits-reduced-inhibition-to-hnav1-4-and-hnav1-5-channels-while-retaining-analgesic-activity
#1
Yijia Xu, Xiangxue Meng, Xue Hou, Jianfang Sun, Xiaohua Kong, Yuqi Sun, Zeyu Liu, Yuanyuan Ma, Ye Niu, Yongbo Song, Yong Cui, Mingyi Zhao, Jinghai Zhang
Scorpion toxins can kill other animals by inducing paralysis and arrhythmia, which limits the potential applications of these agents in the clinical management of diseases. Antitumor-analgesic peptide (AGAP), purified from Buthus martensii Karsch (BmK), has been proved to possess analgesic and antitumor activities. Trp38, a conserved aromatic residue of AGAP, might play an important role in mediating AGAP activities according to the sequence and homology modeling analyses. Therefore, an AGAP mutant W38G was generated, and effects of both AGAP and the mutant W38G were examine by whole-cell patch clamp techniques on the sodium channels hNav1...
September 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28913981/age-dependent-expression-of-nav1-9-channels-in-medial-prefrontal-cortex-mpfc-pyramidal-neurons-in-rats
#2
Maciej Gawlak, Bartłomiej Szulczyk, Adam Berlowski, Katarzyna Grzelka, Anna Stachurska, Justyna Pelka, Katarzyna Czarzasta, Maciej Malecki, Przemyslaw Kurowski, Ewa Nurowska, Pawel Szulczyk
Developmental changes that occur in the prefrontal cortex during adolescence alter behavior. These behavioral alterations likely stem from changes in prefrontal cortex neuronal activity, which may depend on the properties and expression of ion channels. Nav1.9 sodium channels conduct a Na(+) current that is TTX resistant with a low threshold and noninactivating over time. The purpose of this study was to assess the presence of Nav1.9 channels in medial prefrontal cortex (mPFC) layer II and V pyramidal neurons in young (20-day-old), late adolescent (60-day-old) and adult (6-7-month-old) rats...
September 15, 2017: Developmental Neurobiology
https://www.readbyqxmd.com/read/28905186/antidepressants-inhibit-nav1-3-nav1-7-and-nav1-8-neuronal-voltage-gated-sodium-channels-more-potently-than-nav1-2-and-nav1-6-channels-expressed-in-xenopus-oocytes
#3
Takafumi Horishita, Nobuyuki Yanagihara, Susumu Ueno, Dan Okura, Reiko Horishita, Tomoko Minami, Yuichi Ogata, Yuka Sudo, Yasuhito Uezono, Takeyoshi Sata, Takashi Kawasaki
Tricyclic antidepressants (TCAs) and duloxetine are used to treat neuropathic pain. However, the mechanisms underlying their analgesic effects remain unclear. Although many investigators have shown inhibitory effects of antidepressants on voltage-gated sodium channels (Nav) as a possible mechanism of analgesia, to our knowledge, no one has compared effects on the diverse variety of sodium channel α subunits. We investigated the effects of antidepressants on sodium currents in Xenopus oocytes expressing Nav1...
September 14, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28898267/depolarization-of-the-conductance-voltage-relationship-in-the-nav1-5-mutant-e1784k-is-due-to-altered-fast-inactivation
#4
Colin H Peters, Alec Yu, Wandi Zhu, Jonathan R Silva, Peter C Ruben
E1784K is the most common mixed long QT syndrome/Brugada syndrome mutant in the cardiac voltage-gated sodium channel NaV1.5. E1784K shifts the midpoint of the channel conductance-voltage relationship to more depolarized membrane potentials and accelerates the rate of channel fast inactivation. The depolarizing shift in the midpoint of the conductance curve in E1784K is exacerbated by low extracellular pH. We tested whether the E1784K mutant shifts the channel conductance curve to more depolarized membrane potentials by affecting the channel voltage-sensors...
2017: PloS One
https://www.readbyqxmd.com/read/28880874/discovery-and-mode-of-action-of-a-novel-analgesic-%C3%AE-toxin-from-the-african-spider-ceratogyrus-darlingi
#5
Silmara R Sousa, Joshua S Wingerd, Andreas Brust, Christopher Bladen, Lotten Ragnarsson, Volker Herzig, Jennifer R Deuis, Sebastien Dutertre, Irina Vetter, Gerald W Zamponi, Glenn F King, Paul F Alewood, Richard J Lewis
Spider venoms are rich sources of peptidic ion channel modulators with important therapeutical potential. We screened a panel of 60 spider venoms to find modulators of ion channels involved in pain transmission. We isolated, synthesized and pharmacologically characterized Cd1a, a novel peptide from the venom of the spider Ceratogyrus darlingi. Cd1a reversibly paralysed sheep blowflies (PD50 of 1318 pmol/g) and inhibited human Cav2.2 (IC50 2.6 μM) but not Cav1.3 or Cav3.1 (IC50 > 30 μM) in fluorimetric assays...
2017: PloS One
https://www.readbyqxmd.com/read/28880078/the-role-of-disulfide-bond-replacements-in-analogues-of-the-tarantula-toxin-protx-ii-and-their-effects-on-inhibition-of-the-voltage-gated-sodium-ion-channel-nav1-7
#6
Zoë V F Wright, Stephen McCarthy, Rachael Dickman, Francis E Reyes, Silvia Sanchez-Martinez, Adam Cryar, Ian Kilford, Adrian Hall, Andrew K Takle, Maya Topf, Tamir Gonen, Konstantinos Thalassinos, Alethea B Tabor
Spider venom toxins, such as Protoxin-II (ProTx-II), have recently received much attention as selective Nav1.7 channel blockers, with potential to be developed as leads for the treatment of chronic nocioceptive pain. ProTx-II is a 30-amino acid peptide with three disulfide bonds that has been reported to adopt a well-defined inhibitory cystine knot (ICK) scaffold structure. Potential drawbacks with such peptides include poor pharmacodynamics and potential scrambling of the disulfide bonds in vivo. In order to address these issues, in the present study we report the solid-phase synthesis of lanthionine-bridged analogues of ProTx-II, in which one of the three disulfide bridges is replaced with a thioether linkage, and evaluate the biological properties of these analogues...
September 7, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28867800/ciguatoxins-evoke-potent-cgrp-release-by-activation-of-voltage-gated-sodium-channel-subtypes-nav1-9-nav1-7-and-nav1-1
#7
Filip Touska, Simon Sattler, Philipp Malsch, Richard J Lewis, Peter W Reeh, Katharina Zimmermann
Ciguatoxins (CTXs) are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel activator toxins, the etiology of many of its neurosensory symptoms remains unresolved. We recently described that local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals...
August 30, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28837387/crmp2-is-necessary-for-neurofibromatosis-type-1-related-pain
#8
Aubin Moutal, Song Cai, Shizhen Luo, Raphaëlle Voisin, Rajesh Khanna
Neurofibromatosis type 1 (NF1) is one of the most common genetic diseases, affecting roughly 1 in 3000 individuals. As a multisystem disorder, it affects cognitive development, as well as bone, nerve and muscle constitution. Peripheral neuropathy in NF1 constitutes a potentially severe clinical complication and is associated with increased morbidity and mortality. The discovery of effective therapies for Neurofibromatosis type 1 (NF1) pain depends on mechanistic understanding that has been limited, in part, by the relative lack of availability of animal models relevant to NF1 pain...
August 24, 2017: Channels
https://www.readbyqxmd.com/read/28829200/pharmacological-treatment-of-trigeminal-neuralgia
#9
Giulia Di Stefano, Andrea Truini
Unique among the different neuropathic pain conditions, trigeminal neuralgia frequently has an excellent response to some selected drugs, which, on the other hand, often entail disabling side effects. Physicians should be therefore acquainted with the management of these drugs and the few alternative options. Areas covered: This article, based on a systematic literature review, describes the pharmacological options, and indicates the future perspectives for treating trigeminal neuralgia. The article therefore provides current, evidence-based knowledge about the pharmacological treatment of trigeminal neuralgia, and suggests a practical approach to the various drugs, including starting dose, titration and side effects...
September 4, 2017: Expert Review of Neurotherapeutics
https://www.readbyqxmd.com/read/28818462/discovery-of-non-zwitterionic-aryl-sulfonamides-as-nav1-7-inhibitors-with-efficacy-in-preclinical-behavioral-models-and-translational-measures-of-nociceptive-neuron-activation
#10
Yong-Jin Wu, Jason Guernon, Andrea McClure, Guanglin Luo, Ramkumar Rajamani, Alicia Ng, Amy Easton, Amy Newton, Clotilde Bourin, Dawn Parker, Kathleen Mosure, Omar Barnaby, Matthew G Soars, Ronald J Knox, Michele Matchett, Rick Pieschl, James Herrington, Ping Chen, D V Sivarao, Linda J Bristow, Nicholas A Meanwell, Joanne Bronson, Richard Olson, Lorin A Thompson, Carolyn Dzierba
Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons...
August 9, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28804613/novel-derivatives-of-phthalimide-with-potent-anticonvulsant-activity-in-ptz-and-mes-seizure-models
#11
Asghar Davood, Maryam Iman, Hanieh Pouriaiee, Hamed Shafaroodi, Sepideh Akhbari, Leila Azimidoost, Erfan Imani, Somaieh Rahmatpour
OBJECTIVES: Phthalimide-based derivatives have anticonvulsant activity like as phenytoin by inhibition of sodium channel. In our previously research we mentioned about some phthalimide derivatives as potent anticonvulsant agents. MATERIALS AND METHODS: Fourteen analogs of 2-substituted phthalimide pharmacophore were synthesized and then were evaluated for the anticonvulsant activities in pentylenetetrazole-induced seizures (PTZ) and maximal electroshock seizure (MES) models...
April 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28800217/engineering-antibody-reactivity-for-efficient-derivatization-to-generate-nav1-7-inhibitory-gptx-1-peptide-antibody-conjugates
#12
Kaustav Biswas, Thomas E Nixey, Justin K Murray, James R Falsey, Li Yin, Hantao Liu, Jacinthe Gingras, Brian E Hall, Brad Herberich, Jerry Ryan Holder, Hongyan Li, Joseph Ligutti, Min-Hwa Jasmine Lin, Dong Liu, Brian D Soriano, Marcus Soto, Linh Tran, Christopher M Tegley, Anrou Zou, Kannan Gunasekaran, Bryan D Moyer, Liz Doherty, Les P Miranda
The voltage-gated sodium channel NaV1.7 is a genetically-validated pain target under investigation for the development of analgesics. A therapeutic with a less frequent dosing regimen would be of value for treating chronic pain, however functional NaV1.7 targeting antibodies are not known. In this report we describe NaV1.7 inhibitory peptide-antibody conjugates as an alternate construct for potential prolonged channel blockade through chemical derivatization of engineered antibodies. We previously identified NaV1...
August 11, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28769585/%C3%AE-lipoic-acid-suppresses-neuronal-excitability-and-attenuates-colonic-hypersensitivity-to-colorectal-distention-in-diabetic-rats
#13
Yan Sun, Pan-Pan Yang, Zhen-Yuan Song, Yu Feng, Duan-Min Hu, Ji Hu, Guang-Yin Xu, Hong-Hong Zhang
AIM: Patients with long-standing diabetes often demonstrate intestinal dysfunction, characterized as constipation or colonic hypersensitivity. Our previous studies have demonstrated the roles of voltage-gated sodium channels NaV1.7 and NaV1.8 in dorsal root ganglion (DRG) in colonic hypersensitivity of rats with diabetes. This study was designed to determine roles of antioxidant α-lipoic acid (ALA) on sodium channel activities and colonic hypersensitivity of rats with diabetes. METHODS: Streptozotocin was used to induce diabetes in adult female rats...
2017: Journal of Pain Research
https://www.readbyqxmd.com/read/28751508/between-fire-and-ice-refractory-hypothermia-and-warmth-induced-pain-in-inherited-erythromelalgia
#14
See Wan Tham, Li Li, Philip Effraim, Stephen Waxman
Inherited erythromelalgia (IEM) is a well-described pain disorder caused by mutations of sodium channel Nav1.7, a peripheral channel expressed within dorsal root ganglion and the sympathetic ganglion neurons. Clinically, IEM is characterised by paroxysmal attacks of severe pain, usually in the distal extremities, triggered by warmth or exercise. Pain is not adequately treated by existing pharmacological agents. Individuals with IEM classically cool their limbs for relief, in some cases resulting in tissue injury...
July 26, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/28710467/human-ipsc-derived-cardiomyocytes-cultured-in-3d-engineered-heart-tissue-show-physiological-upstroke-velocity-and-sodium-current-density
#15
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
#16
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...
August 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28683073/high-throughput-electrophysiological-assays-for-voltage-gated-ion-channels-using-syncropatch-768pe
#17
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
#18
Nigel A 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 R G Galan, Steven 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 A Stupple, Christopher W West
A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype 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 nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics...
August 10, 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
#19
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
#20
Ramkumar Rajamani, Sophie Wu, Iyoncy Rodrigo, Mian Gao, Simon Low, Lisa Megson, David Wensel, Rick L Pieschl, Debra J Post-Munson, John Watson, David R Langley, Michael K Ahlijanian, Linda J Bristow, James Herrington
The NaV1.7 voltage-gated sodium channel is implicated in human pain perception by genetics. Rare gain of function mutations in NaV1.7 lead to spontaneous pain in humans whereas loss of function mutations results in congenital insensitivity to pain. 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 surrogate target strategy approach employing chimeras with the bacterial channel NaVAb...
September 2017: Molecular Pharmacology
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